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  • 1.
    Dakhel, Soran
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Davies, Wayne I. L.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Joseph, Justin V.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Tomar, Tushar
    PamGene International B.V, 's-Hertogenbosch, Wolvenhoek 10, Netherlands.
    Remeseiro, Silvia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Chick fetal organ spheroids as a model to study development and disease2021In: BMC Molecular and Cell Biology, E-ISSN 2661-8850, Vol. 22, no 1, article id 37Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Organ culture models have been used over the past few decades to study development and disease. The in vitro three-dimensional (3D) culture system of organoids is well known, however, these 3D systems are both costly and difficult to culture and maintain. As such, less expensive, faster and less complex methods to maintain 3D cell culture models would complement the use of organoids. Chick embryos have been used as a model to study human biology for centuries, with many fundamental discoveries as a result. These include cell type induction, cell competence, plasticity and contact inhibition, which indicates the relevance of using chick embryos when studying developmental biology and disease mechanisms.

    RESULTS: Here, we present an updated protocol that enables time efficient, cost effective and long-term expansion of fetal organ spheroids (FOSs) from chick embryos. Utilizing this protocol, we generated FOSs in an anchorage-independent growth pattern from seven different organs, including brain, lung, heart, liver, stomach, intestine and epidermis. These three-dimensional (3D) structures recapitulate many cellular and structural aspects of their in vivo counterpart organs and serve as a useful developmental model. In addition, we show a functional application of FOSs to analyze cell-cell interaction and cell invasion patterns as observed in cancer.

    CONCLUSION: The establishment of a broad ranging and highly effective method to generate FOSs from different organs was successful in terms of the formation of healthy, proliferating 3D organ spheroids that exhibited organ-like characteristics. Potential applications of chick FOSs are their use in studies of cell-to-cell contact, cell fusion and tumor invasion under defined conditions. Future studies will reveal whether chick FOSs also can be applicable in scientific areas such as viral infections, drug screening, cancer diagnostics and/or tissue engineering.

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  • 2.
    Davies, Wayne I. L.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sghari, Soufien
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Upton, Brian A.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lang, Richard A.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Distinct opsin 3 (Opn3) expression in the developing nervous system during mammalian embryogenesis2021In: eNeuro, E-ISSN 2373-2822, Vol. 8, no 5, article id ENEURO.0141-21.2021Article in journal (Refereed)
    Abstract [en]

    Opsin 3 (Opn3) is highly expressed in the adult brain, however, information for spatial and temporal expression patterns during embryogenesis is significantly lacking. Here, an Opn3-eGFP reporter mouse line was used to monitor cell body expression and axonal projections during embryonic and early postnatal to adult stages. By applying 2D and 3D fluorescence imaging techniques, we have identified the onset of Opn3 expression, which predominantly occurred during embryonic stages, in various structures during brain/head development. In ad-dition, this study defines over twenty Opn3-eGFP-positive neural structures never reported before. Opn3-eGFP was first observed at E9.5 in neural regions, including the ganglia that will ultimately form the trigeminal, facial and vestibulocochlear cranial nerves (CNs). As development proceeds, expanded Opn3-eGFP expression coincided with the formation and maturation of critical components of the central and peripheral nervous systems (CNS, PNS), including various motor-sensory tracts, such as the dorsal column-medial lemniscus (DCML) sensory tract, and olfactory, acoustic, and optic tracts. The widespread, yet distinct, detection of Opn3-eGFP already at early embryonic stages suggests that Opn3 might play important functional roles in the developing brain and spinal cord to regulate multiple motor and sensory circuitry systems, including proprio-ception, nociception, ocular movement, and olfaction, as well as memory, mood, and emotion. This study presents a crucial blueprint from which to investigate autonomic and cognitive opsin-dependent neural development and resultant behaviors under physiological and pathophysiological conditions.

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  • 3.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The lens: a classical model of embryonic induction providing new insights into cell determination in early development2011In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 366, no 1568, p. 1193-1203Article in journal (Refereed)
    Abstract [en]

    The lens was the first tissue in which the concept of embryonic induction was demonstrated. For many years lens induction was thought to occur at the time the optic vesicle and lens placode came in contact. Since then, studies have revealed that lens placodal progenitor cells are specified already at gastrula stages, much earlier than previously believed, and independent of optic vesicle interactions. In this review, I will focus on how individual signalling molecules, in particular BMP, FGF, Wnt and Shh, regulate the initial specification of lens placodal cells and the progressive development of lens cells. I will discuss recent work that has shed light on the combination of signalling molecules and the molecular interactions that affect lens specification and proper lens formation. I will also discuss proposed tissue interactions important for lens development. A greater knowledge of the molecular interactions during lens induction is likely to have practical benefits in understanding the causes and consequences of lens diseases. Moreover, knowledge regarding lens induction is providing fundamental important insights into inductive processes in development in general.

  • 4.
    Gunhaga, Lena
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jessell, T M
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sonic hedgehog signaling at gastrula stages specifies ventral telencephalic cells in the chick embryo2000In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 127, no 15, p. 3283-3293Article in journal (Refereed)
    Abstract [en]

    A secreted signaling factor, Sonic hedgehog (Shh), has a crucial role in the generation of ventral cell types along the entire rostrocaudal axis of the neural tube. At caudal levels of the neuraxis, Shh is secreted by the notochord and floor plate during the period that ventral cell fates are specified. At anterior prosencephalic levels that give rise to the telencephalon, however, neither the prechordal mesoderm nor the ventral neural tube expresses Shh at the time that the overt ventral character of the telencephalon becomes evident. Thus, the precise role and timing of Shh signaling relevant to the specification of ventral telencephalic identity remains unclear. By analysing neural cell differentiation in chick neural plate explants we provide evidence that neural cells acquire molecular properties characteristic of the ventral telencephalon in response to Shh signals derived from the anterior primitive streak/Hensen's node region at gastrula stages. Exposure of prospective anterior prosencephalic cells to Shh at this early stage is sufficient to initiate a temporal program of differentiation that parallels that of neurons generated normally in the medial ganglionic eminence subdivision of the ventral telencephalon.

  • 5.
    Gunhaga, Lena
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Marklund, Matthew
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sjödal, My
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hsieh, Jen-Chih
    Jessell, Thomas M
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Specification of dorsal telencephalic character by sequential Wnt and FGF signaling.2003In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, no 7, p. 701-707Article in journal (Refereed)
    Abstract [en]

    Dorsoventral patterning of the telencephalon is established early in forebrain development and underlies many of the regional subdivisions that are critical to the later organization of neural circuits in the cerebral cortex and basal ganglia. Sonic hedgehog (Shh) is involved in the generation of the ventral-most telencephalic cells, but the identity of the extrinsic signal(s) that induce dorsal character in telencephalic cells is not known. Here we show in chick embryos that sequential Wnt and fibroblast growth factor (FGF) signaling specifies cells of dorsal telencephalic character.

  • 6. Huang, Jie
    et al.
    Liu, Ying
    Filas, Benjamen
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Beebe, David C.
    Negative and positive auto-regulation of BMP expression in early eye development2015In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 407, no 2, p. 256-264Article in journal (Refereed)
    Abstract [en]

    Previous results have shown that Bone Morphogenetic Protein (BMP) signaling is essential for lens specification and differentiation. How BMP signals are regulated in the prospective lens ectoderm is not well defined. To address this issue we have modulated BMP activity in a chicken embryo pre-lens ectoderm explant assay, and also studied transgenic mice, in which the type I BMP receptors, Bmpr1a and Acvr1, are deleted from the prospective lens ectoderm. Our results show that chicken embryo pre-lens ectoderm cells express BMPs and require BMP signaling for lens specification in vitro, and that in vivo inhibition of BMP signals in the mouse prospective lens ectoderm interrupts lens placode formation and prevents lens invagination. Furthermore, our results provide evidence that BMP expression is negatively auto-regulated in the lens-forming ectoderm, decreasing when the tissue is exposed to exogenous BMPs and increasing when BMP signaling is prevented. In addition, eyes lacking BMP receptors in the prospective lens placode develop coloboma in the adjacent wild type optic cup. In these eyes, Bmp7 expression increases in the ventral optic cup and the normal dorsal-ventral gradient of BMP signaling in the optic cup is disrupted. Pax2 becomes undetectable and expression of Sfrp2 increases in the ventral optic cup, suggesting that increased BMP signaling alter their expression, resulting in failure to close the optic fissure. In summary, our results suggest that negative and positive auto-regulation of BMP expression is important to regulate early eye development. 

  • 7. Jarrin, Miguel
    et al.
    Mansergh, Fiona C
    Boulton, Michael E
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Wride, Michael A
    Survivin expression is associated with lens epithelial cell proliferation and fiber cell differentiation2012In: Molecular Vision, ISSN 1090-0535, Vol. 18, no 283-86, p. 2758-2769Article in journal (Refereed)
    Abstract [en]

    Purpose: Survivin (Birc5) is the smallest member of the inhibitor of apoptosis (IAP) protein family, which regulates the cell cycle/apoptosis balance. The purpose of this study was to examine Survivin expression in the embryonic chick lens, in chick lens epithelial cell cultures, and in the postnatal mouse lens.

    Methods: Survivin expression was examined using a combination of quantitative real-time polymerase chain reaction, western blotting, and immunocytochemistry. To correlate Survivin expression with the timing of proliferation, we determined the profile of cell proliferation in the developing lens using the cell cycle marker proliferating cell nuclear antigen (PCNA) in quantitative western blotting and immunocytochemistry studies. We also examined the expression of PCNA and the extent of denucleation using terminal deoxynucleotidyl transferase (TdT)-mediated biotin-dUTP nick-end labeling (TUNEL) of lentoids (lens fiber-like cells) during chick lens epithelial cell differentiation in vitro.

    Results: At embryonic day (ED) 4, Survivin immunostaining was present in two pools in lens epithelial cells and fiber cells: cytoplasmic and nuclear. The nuclear staining became more pronounced as the lens epithelial cells differentiated into lens fiber cells. At ED12, Survivin staining was observed in lens fiber cell nuclei containing marginalized chromatin, indicative of early denucleation events. Using western blotting, Survivin expression peaked at ED6, diminishing thereafter. This profile of expression correlated with the events in chick lens epithelial cell cultures: i) increased Survivin expression was associated with an increase in PCNA staining up to day 6 of culture and ii) downregulation of Survivin expression at day 8 of culture was coincident with a dramatic decrease in PCNA staining and an increase in TdT-mediated biotin-dUTP nick-end labeling in lentoids. In early postnatal mouse lenses, Survivin and PCNA were highly expressed and decreased thereafter during postnatal lens maturation.

    Conclusions: Survivin is expressed during chick and mouse lens development and in chick lens epithelial cell cultures. High levels of Survivin expression correlated with high rates of proliferation of lens epithelial cells at early stages of development. Downregulation of Survivin expression with development and its progressive localization to the nuclei of lens fiber cells was coincident with a decrease in cell proliferation and increased denucleation in differentiating lens fiber cells. These studies suggest an important role for Survivin as a dual regulator of lens epithelial cell proliferation and lens fiber cell differentiation.

  • 8.
    Jarrin, Miguel
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pandit, Tanushree
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 16, p. 3266-3274Article in journal (Refereed)
    Abstract [en]

    In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals.

  • 9.
    Jidigam, Vijay
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Role of BMP signaling on cytoskeleton elements in the sensory placode invagination2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, article id P1653Article in journal (Other academic)
  • 10.
    Jidigam, Vijay K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Development of cranial placodes: insights from studies in chick2013In: Development, Growth and Differentiation, ISSN 0012-1592, E-ISSN 1440-169X, Vol. 55, no 1, p. 79-95Article, review/survey (Refereed)
    Abstract [en]

    This review focuses on how research, using chick as a model system, has contributed to our knowledge regarding the development of cranial placodes. This review highlights when and how molecular signaling events regulate early specification of placodal progenitor cells, as well as the development of individual placodes including morphological movements. In addition, we briefly describe various techniques used in chick that are important for studies in cell and developmental biology.

  • 11.
    Jidigam, Vijay K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Srinivasan, Raghuraman C.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Patthey, Cedric
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Apical constriction and epithelial invagination are regulated by BMP activity2015In: Biology open, ISSN 2046-6390, Vol. 4, no 12, p. 1782-1791Article in journal (Refereed)
    Abstract [en]

    Epithelial invagination is a morphological process in which flat cell sheets transform into three-dimensional structures through bending of the tissue. It is accompanied by apical constriction, in which the apical cell surface is reduced in relation to the basal cell surface. Although much is known about the intra-cellular molecular machinery driving apical constriction and epithelial invagination, information of how extra-cellular signals affect these processes remains insufficient. In this study we have established several in vivo assays of placodal invagination to explore whether the external signal BMP regulates processes connected to epithelial invagination. By inhibiting BMP activity in prospective cranial placodes, we provide evidence that BMP signals are required for RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination. The failure of placode invagination after BMP inhibition appears to be a direct consequence of disrupted apical accumulation of RhoA and F-actin, rather than changes in cell death or proliferation. In addition, our results show that epithelial invagination and acquisition of placode-specific identities are two distinct and separable developmental processes. In summary, our results provide evidence that BMP signals promote epithelial invagination by acting upstream of the intracellular molecular machinery that drives apical constriction and cell elongation.

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  • 12.
    Karthikeyan, Ramanujam
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Davies, Wayne I. L.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne Campus, VIC, Melbourne, Australia.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Non-image-forming functional roles of OPN3, OPN4 and OPN5 photopigments2023In: Journal of Photochemistry and Photobiology, E-ISSN 2666-4690, Vol. 15, article id 100177Article in journal (Refereed)
    Abstract [en]

    Detecting different wavelengths and intensities of environmental light is crucial for the survival of many animals. In response, a multiplicity of opsins (a special group of photosensitive G protein-coupled receptors), when combined with a retinal chromophore, is able to directly detect light and initiate different downstream phototransduction signaling cascades. Although avian studies from the 1930s suggested the presence of deep brain photoreceptors that could respond to seasonal changes in the light/dark cycle, it was only a few decades ago that photopigments other than those found in the visual system (i.e. rods and cones) were identified as functional photoreceptors. It is now established that several classes of non-visual photoreceptors and the photopigments they express, in lower vertebrates to higher mammals alike, can regulate a plethora of mechanisms that function outside of vision. These include the synchronization of light/dark cycles with biological/cellular rhythms of the body (i.e. photoentrainment); melanogenesis in dermal tissues; thermoregulation in adipose tissue; embryonic eye development; smooth muscle relaxation; and the development of certain cancers. These and other mechanisms have been shown, in part at least, to be controlled by the expression of three important non-visual opsin genes, namely OPN3, OPN4 and OPN5, although other vertebrate opsin classes exist, many with unknown or unclear functional roles assigned to them presently. Specifically, these three opsins have been shown to be expressed during early embryogenesis and throughout adulthood, which will be discussed here. Moreover, this review highlights recent studies that focus on several key non-image-forming functional roles of OPN3, OPN4 and OPN5, and in particular those that impact photoreception in developing structures and pathways, as well as in adulthood.

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  • 13.
    Lorén, Christina E
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schrader, John W
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    FGF signals induce Caprin2 expression in the vertebrate lens.2009In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 77, no 4, p. 386-394Article in journal (Refereed)
    Abstract [en]

    The lens of the eye is derived from the non-neural ectoderm situated next to the optic vesicle. Fibroblast growth factor (FGF) signals play a major role at various stages of vertebrate lens development ranging from induction and proliferation to differentiation. Less is however known about the identity of genes that are induced by FGF activity within the lens. We have isolated and characterized mouse cytoplasmic activation/proliferation-associated protein-2 (Caprin2), with domains belonging to both the Caprin family and the C1q and tumour necrosis factor (TNF) super-family. Here we show that Caprin2 is expressed in the developing vertebrate lens in mouse and chick, and that Caprin2 expression is up-regulated in primary lens fiber cells, after the induction of crystallins the earliest known markers for differentiated lens fiber cells. Caprin2 is subsequently down-regulated in the centre of the lens at the time and at the position of the first fiber cell denucleation and terminal differentiation. In vitro analyses of lens fiber cell differentiation provide evidence that FGF activity emanating from neighboring prospective retinal cells is required and that FGF8 activity is sufficient to induce Caprin2 in lens fiber cells. These results not only provide evidence that FGF signals induce the newly characterized protein Caprin2 in the lens, but also support the general idea that FGF signals are required for lens fiber cell differentiation.

  • 14.
    Maier, Esther
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Hanna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A balance of BMP and notch activity regulates neurogenesis and olfactory nerve formation2011In: PloS one, ISSN 1932-6203, Vol. 6, no 2, p. e17379-Article in journal (Refereed)
    Abstract [en]

    Although the function of the adult olfactory system has been thoroughly studied, the molecular mechanisms regulating the initial formation of the olfactory nerve, the first cranial nerve, remain poorly defined. Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells. We show that this reduction of epithelial and migratory neurons is followed by a subsequent failure or complete absence of olfactory nerve formation. These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract. Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

  • 15.
    Maier, Esther
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Hanna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Fernandes, Marie
    Paek, Hunki
    Hébert, Jean M
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Opposing Fgf and Bmp activities regulate the specification of olfactory sensory and respiratory epithelial cell fates.2010In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 137, no 10, p. 1601-1611Article in journal (Refereed)
    Abstract [en]

    The olfactory sensory epithelium and the respiratory epithelium are derived from the olfactory placode. However, the molecular mechanisms regulating the differential specification of the sensory and the respiratory epithelium have remained undefined. To address this issue, we first identified Msx1/2 and Id3 as markers for respiratory epithelial cells by performing quail chick transplantation studies. Next, we established chick explant and intact chick embryo assays of sensory/respiratory epithelial cell differentiation and analyzed two mice mutants deleted of Bmpr1a;Bmpr1b or Fgfr1;Fgfr2 in the olfactory placode. In this study, we provide evidence that in both chick and mouse, Bmp signals promote respiratory epithelial character, whereas Fgf signals are required for the generation of sensory epithelial cells. Moreover, olfactory placodal cells can switch between sensory and respiratory epithelial cell fates in response to Fgf and Bmp activity, respectively. Our results provide evidence that Fgf activity suppresses and restricts the ability of Bmp signals to induce respiratory cell fate in the nasal epithelium. In addition, we show that in both chick and mouse the lack of Bmp or Fgf activity results in disturbed placodal invagination; however, the fate of cells in the remaining olfactory epithelium is independent of morphological movements related to invagination. In summary, we present a conserved mechanism in amniotes in which Bmp and Fgf signals act in an opposing manner to regulate the respiratory versus sensory epithelial cell fate decision.

  • 16.
    Marklund, Matthew
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sjödal, My
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Beehler, Blake C
    Jessell, Thomas M
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Retinoic acid signalling specifies intermediate character in the developing telencephalon.2004In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 17, p. 4323-4332Article in journal (Refereed)
    Abstract [en]

    The organisation of the telencephalon into its major structures depends on its early regionalisation along the dorsoventral axis. Previous studies have provided evidence that sonic hedgehog (SHH) is required for the generation of telencephalic cells of ventral character, and that sequential WNT and fibroblast growth factor (FGF) signalling specifies cells of dorsal telencephalic character. However, the signalling mechanisms that specify telencephalic cells of an intermediate character remain to be defined. We provide evidence here that retinoic acid has a crucial role in specifying telencephalic progenitor cells of intermediate character.

  • 17.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Slekiene, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Lithuania.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    CAM-Delam Assay to Score Metastatic Properties by Quantifying Delamination and Invasion Capacity of Cancer Cells2022In: Journal of Visualized Experiments, E-ISSN 1940-087X, Vol. 2022, no 184, article id e64025Article in journal (Refereed)
    Abstract [en]

    The major cause of cancer-related deaths is metastasis formation (i.e., when cancer cells spread from the primary tumor to distant organs and form secondary tumors). Delamination, defined as the degradation of the basal lamina and basement membrane, is the initial process that facilitates the transmigration and spread of cancer cells to other tissues and organs. Scoring the delamination capacity of cancer cells would indicate the metastatic potential of these cells. We have developed a standardized method, the ex ovo CAM-Delam assay, to visualize and quantify the ability of cancer cells to delaminate and invade, thereby being able to assess metastatic aggressiveness. Briefly, the CAM-Delam method includes seeding cancer cells in silicone rings on the chick chorioallantoic membrane (CAM) at embryonic day 10, followed by incubation from hours to a few days. The CAM-Delam assay includes the use of an internal humidified chamber during chick embryo incubation. This novel approach increased embryo survival from 10%-50% to 80%-90%, which resolved previous technical problems with low embryo survival rates in different CAM assays. Next, the CAM samples with associated cancer cell clusters were isolated, fixed, and frozen. Finally, cryostat-sectioned samples were visualized and analyzed for basement membrane damage and cancer cell invasion using immunohistochemistry. By evaluating various known metastatic and non-metastatic cancer cell lines designed to express green fluorescent protein (GFP), the CAM-Delam quantitative results showed that the delamination capacity patterns reflect metastatic aggressiveness and can be scored into four categories. Future use of this assay, apart from quantifying delamination capacity as an indication of metastatic aggressiveness, is to unravel the molecular mechanisms that control delamination, invasion, the formation of micrometastases, and changes in the tumor microenvironment.

  • 18.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Slekiene, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Patthey, Cedric
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Extensive apoptosis during the formation of the terminal nerve ganglion by olfactory placode-derived cells with distinct molecular markers2019In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 110, p. 8-16Article in journal (Refereed)
    Abstract [en]

    The terminal nerve ganglion (TNG) is a well-known structure of the peripheral nervous system in cartilaginous and teleost fishes. It derives from the olfactory placode during embryonic development. While the differentiation and migration of gonadotropin releasing hormone (GnRH)-expressing neurons from the olfactory placode has been well documented, the TNG has been neglected in birds and mammals, and its development is less well described. Here we describe the formation of a ganglion-like structure from migratory olfactory placodal cells in chicken. The TNG is surrounded by neural crest cells, but in contrast to other cranial sensory ganglia, we observed no neural crest corridor, and olfactory unsheathing cells appear only after the onset of neuronal migration. We identified Isl1 and Lhx2 as two transcription factors that label neuronal subpopulations in the forming TNG, distinct from GnRH1(+) cells, thereby revealing a diversity of cell types during the formation of the TNG. We also provide evidence for extensive apoptosis in the terminal nerve ganglion shortly after its formation, but not in other cranial sensory ganglia. Moreover, at later stages placode-derived neurons expressing GnRH1, Isl1 and/or Lhx2 become incorporated in the telencephalon. The integration of TNG neurons into the telencephalon together with the earlier widespread apoptosis in the TNG might be an explanation why the TNG in mammals and birds is much smaller compared to other vertebrates.

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  • 19.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Slekiene, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jonasson, Anna-Karin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    CAM-Delam: an in vivo approach to visualize and quantify the delamination and invasion capacity of human cancer cells2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 10472Article in journal (Refereed)
    Abstract [en]

    The development of metastases is the major cause of cancer related death. To develop a standardized method that define the ability of human cancer cells to degrade the basement membrane, e.g. the delamination capacity, is of importance to assess metastatic aggressiveness. We now present the in vivo CAM-Delam assay to visualize and quantify the ability of human cancer cells to delaminate and invade. The method includes seeding cancer cells on the chick chorioallantoic membrane (CAM), followed by the evaluation of cancer-induced delamination and potential invasion within hours to a few days. By testing a range of human cancer cell lines in the CAM-Delam assay, our results show that the delamination capacity can be divided into four categories and used to quantify metastatic aggressiveness. Our results emphasize the usefulness of this assay for quantifying delamination capacity as a measurement of metastatic aggressiveness, and in unraveling the molecular mechanisms that regulate delamination, invasion, formation of micro-metastases and modulations of the tumor microenvironment. This method will be useful in both the preclinical and clinical characterization of tumor biopsies, and in the validation of compounds that may improve survival in metastatic cancer.

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  • 20.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Wittmann, Walter
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jidigam, Vijay K.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mercurio, Sara
    Bertolini, Jessica A.
    Sghari, Soufien
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bose, Raj
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Patthey, Cedric
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nicolis, Silvia K.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 2, article id dev153791Article in journal (Refereed)
    Abstract [en]

    The transcription factor Sox2 is necessary to maintain pluripotency of embryonic stem cells, and to regulate neural development. Neurogenesis in the vertebrate olfactory epithelium persists from embryonic stages through adulthood. The role Sox2 plays for the development of the olfactory epithelium and neurogenesis within has, however, not been determined. Here, by analysing Sox2 conditional knockout mouse embryos and chick embryos deprived of Sox2 in the olfactory epithelium using CRISPR-Cas9, we show that Sox2 activity is crucial for the induction of the neural progenitor gene Hes5 and for subsequent differentiation of the neuronal lineage. Our results also suggest that Sox2 activity promotes the neurogenic domain in the nasal epithelium by restricting Bmp4 expression. The Sox2-deficient olfactory epithelium displays diminished cell cycle progression and proliferation, a dramatic increase in apoptosis and finally olfactory pit atrophy. Moreover, chromatin immunoprecipitation data show that Sox2 directly binds to the Hes5 promoter in both the PNS and CNS. Taken together, our results indicate that Sox2 is essential to establish, maintain and expand the neuronal progenitor pool by suppressing Bmp4 and upregulating Hes5 expression.

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  • 21.
    Pandit, Tanushree
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jidigam, Vijay K
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    BMP-induced L-Maf regulates subsequent BMP-independent differentiation of primary lens fibre cells2011In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 240, no 8, p. 1917-1928Article in journal (Refereed)
    Abstract [en]

    Bone morphogenetic protein (BMP) signals are essential for lens development. However, the temporal requirement of BMP activity during early events of lens development has remained elusive. To investigate this question, we have used gain- and loss-of-function analyses in chick explant and intact embryo assays. Here, we show that BMP activity is both required and sufficient to induce L-Maf expression, whereas the onset of δ-crystallin and initial elongation of primary lens fibre cells are BMP-independent. Moreover, before lens placode formation and L-Maf onset, but not after, prospective lens placodal cells can switch to an olfactory placodal fate in response to decreased BMP activity. In addition, L-Maf is sufficient to up-regulate δ-crystallin independent of BMP signals. Taken together, these results show that before L-Maf induction BMP activity is required for lens specification, whereas after L-Maf up-regulation, the early differentiation of primary lens fibre cells occurs independent of BMP signals.

  • 22.
    Pandit, Tanushree
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jidigam, Vijay Kumar
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Patthey, Cedric
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Neural retina identity is specified by lens-derived BMP signals2015In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 142, no 10, p. 1850-1859Article in journal (Refereed)
    Abstract [en]

    The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity.

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  • 23.
    Patthey, Cedric
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Signaling pathways regulating ectodermal cell fate choices2014In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 321, no 1, p. 11-16Article, review/survey (Refereed)
    Abstract [en]

    Although embryonic patterning and early development of the nervous system have been studied for decades, our understanding of how signals instruct ectodermal derivatives to acquire specific identities has only recently started to form a coherent picture. In this mini-review, we summarize recent findings and models of how a handful of well-known secreted signals influence progenitor cells in successive binary decisions to adopt various cell type specific differentiation programs.

  • 24.
    Patthey, Cedric
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Specification and regionalisation of the neural plate border2011In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 34, no 10, p. 1516-1528Article in journal (Refereed)
    Abstract [en]

    During early vertebrate development, the embryonic ectoderm becomes subdivided into neural, neural plate border (border) and epidermal regions. The nervous system is derived from the neural and border domains which, respectively, give rise to the central and peripheral nervous systems. To better understand the functional nervous system we need to know how individual neurons are specified and connected. Our understanding of the early development of the peripheral nervous system has been lagging compared to knowledge regarding central nervous system and epidermal cell lineage decision. Recent advances have shown when and how the specification of border cells is initiated. One important insight is that border specification is already initiated at blastula stages, and can be molecularly and temporally distinguished from rostrocaudal regionalisation of the border. From findings in several species, it is clear that Wnt, Bone Morphogenetic Protein and Fibroblast Growth Factor signals play important roles during the specification and regionalisation of the border. In this review, we highlight the individual roles of these signals and compare models of border specification, including a new model that describes how temporal coordination and epistatic interactions of extracellular signals result in the specification and regionalisation of border cells.

  • 25.
    Patthey, Cédric
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Wnt-regulated temporal control of BMP exposure directs the choice between neural plate border and epidermal fate2009In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 136, no 1, p. 73-83Article in journal (Refereed)
    Abstract [en]

    The non-neural ectoderm is divided into neural plate border and epidermal cells. At early blastula stages, Wnt and BMP signals interact to induce epidermal fate, but when and how cells initially acquire neural plate border fate remains poorly defined. We now provide evidence in chick that the specification of neural plate border cells is initiated at the late blastula stage and requires both Wnt and BMP signals. Our results indicate, however, that at this stage BMP signals can induce neural plate border cells only when Wnt activity is blocked, and that the two signals in combination generate epidermal cells. We also provide evidence that Wnt signals do not play an instructive role in the generation of neural plate border cells, but promote their generation by inducing BMP gene expression, which avoids early simultaneous exposure to the two signals and generates neural plate border instead of epidermal cells. Thus, specification of neural plate border cells is mediated by a novel Wnt-regulated BMP-mediated temporal patterning mechanism.

  • 26.
    Patthey, Cédric
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Early development of the central and peripheral nervous systems is coordinated by Wnt and BMP signals2008In: PloS one, ISSN 1932-6203, Vol. 3, no 2, p. e1625-Article in journal (Refereed)
  • 27.
    Sghari, Soufien
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Davies, Wayne I. L.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris2020In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 61, no 11, article id 5Article in journal (Refereed)
    Abstract [en]

    PURPOSE. In mammals, pupil constriction and dilation form the pupillary light reflex (PLR), which is mediated by both brain-regulated (parasympathetic) and local iris-driven reflexes. To better understand the cellular mechanisms that regulate pupil physiological dynamics via central and local photoreception, we have examined the regulation of the PLR via parasympathetic and local activation, respectively.

    METHODS. In this study, the PLR was examined in mouse enucleated eyes ex vivo in real-time under different ionic conditions in response to acetylcholine and/or blue light (480 nm). The use of pupillometry recordings captured the relaxation, contraction, and pupil escape (redilation) processes for 10 minutes up to 1 hour.

    RESULTS. Among others, our results show that ryanodine receptor channels are the main driver for iridal stimulation-contraction coupling, in which extracellular influx of Ca2+ is required for amplification of pupil constriction. Both local and parasympathetic iridal activations are necessary, but not sufficient for sustained pupil constriction. Moreover, the degree of membrane potential repolarization in the dark is correlated with the latency and velocity of iridal constriction. Furthermore, pupil escape is driven by membrane potential hyperpolarization where voltage-gated potassium channels play a crucial role.

    CONCLUSIONS. Together, this study presents new mechanisms regulating synchronized pupil dilation and contraction, sustained pupil constriction, iridal stimulation-contraction coupling, and pupil escape.

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  • 28.
    Sghari, Soufien
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Temporal Requirement of Mab21l2 During Eye Development in Chick Reveals Stage-Dependent Functions for Retinogenesis2018In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 10, p. 3869-3878Article in journal (Refereed)
    Abstract [en]

    Different missense mutations in the single exon gene Mab21l2 have been identified in unrelated families with various bilateral eye malformations, including microphthalmia, anophthalmia, and coloboma, but the molecular function of Mab21l2 during eye development still remains largely unknown. METHODS. We have established an in vivo Mab21l2-deficient eye development model in chick, by using a Mab21l2 RNA interference construct that we electroporated in ovo in prospective retinal cells. In addition, we designed a Mab21l2 gain-of-function electroporation vector. Mab21l2-modulated retinas were analyzed on consecutive sections in terms of morphology, and molecular markers for apoptosis, cell proliferation, and retinogenesis. RESULTS. Our Mab21l2-deficient chick model mimics human ocular phenotypes. When Mab21l2 is downregulated prior to optic vesicle formation, the embryos develop anophthalmia, and Mab21l2 inhibition by optic cup stages results in a microphthalmic colobomatous phenotype. Our results show that inhibition of Mab21l2 affects cell proliferation, cell cycle exit, and the expression of Atoh7/Ath5, NeuroD4/Ath3, Isl1, Pax6, AP-2a, and Prox1. In addition, Mab21l2 overexpression hampers cell cycle exit and differentiation of retinal progenitor cells (RPCs). CONCLUSIONS. Our results highlight the importance of a regulated temporal expression of Mab21l2 during eye development: At early stages, Mab21l2 is required to maintain RPC proliferation and expansion of cell number; before retinogenesis, a decrease in Mab21l2 expression in proliferating RPCs is required for cell cycle exit and differentiation; during retinogenesis, Mab21l2 is chronologically upregulated in RGCs, followed by differentiated horizontal and amacrine cells and cone photoreceptor cells.

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  • 29.
    Wang, Tianyan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sarwar, Martuza
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Whitchurch, Jonathan B.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Collins, Hilary M.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Green, Tami
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Amjad, Ali
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Roberts, Christopher J.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Morris, Ryan D.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Pharmacy, Uppsala University, Uppsala, Sweden.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    El-Schich, Zahra
    Department of Biomedical Science, Malmö University, Malmö, Sweden.
    Wingren, Anette G.
    Department of Biomedical Science, Malmö University, Malmö, Sweden.
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Mongan, Nigel P.
    School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom; Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Heery, David M.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Biomedical Science, Malmö University, Malmö, Sweden; Department of Translational Medicine, Lund University, Clinical Research Centre in Malmö, Malmö, Sweden.
    PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer2022In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 798590Article in journal (Refereed)
    Abstract [en]

    PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

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  • 30.
    Wittmann, Walter
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Iulianella, Angelo
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Cux2 acts as a critical regulator for neurogenesis in the olfactory epithelium of vertebrates2014In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 388, no 1, p. 35-47Article in journal (Refereed)
    Abstract [en]

    Signaling pathways and transcription factors are crucial regulators of vertebrate neurogenesis, exerting their function in a spatial and temporal manner. Despite recent advances in our understanding of the molecular regulation of embryonic neurogenesis, little is known regarding how different signaling pathways interact to tightly regulate this process during the development of neuroepithelia. To address this, we have investigated the events lying upstream and downstream of a key neurogenic factor, the Cut-like homeodomain transcription factor-2 (Cux2), during embryonic neurogenesis in chick and mouse. By using the olfactory epithelium as a model for neurogenesis we have analyzed mouse embryos deficient in Cux2, as well as chick embryos exposed to Cux2 silencing (si) RNA or a Cux2 over-expression construct. We provide evidence that enhanced BMP activity increases Cux2 expression and suppresses olfactory neurogenesis in the chick olfactory epithelium. In addition, our results show that up-regulation of Cux2, either BMP-induced or ectopically over-expressed, reduce Delta1 expression and suppress proliferation. Interestingly, the loss of Cux2 activity, using mutant mice or siRNA in chick, also diminishes neurogenesis, Notch activity and cell proliferation in the olfactory epithelium. Our results suggest that controlled low levels of Cux2 activity are necessary for proper Notch signaling, maintenance of the proliferative pool and ongoing neurogenesis in the olfactory epithelium. Thus, we demonstrate a novel conserved mechanism in vertebrates in which levels of Cux2 activity play an important role for ongoing neurogenesis in the olfactory epithelium. (C) 2014 The Authors. Published by Elsevier Inc.

  • 31.
    Wittmann, Walter
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schimmang, Thomas
    Univ Valladolid, Inst Biol & Mol Genet, Valladolid 47003, Spain.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Progressive effects of N-myc deficiency on proliferation, neurogenesis, and morphogenesis in the olfactory epithelium2014In: Developmental Neurobiology, ISSN 1932-8451, E-ISSN 1932-846X, Vol. 74, no 6, p. 643-656Article in journal (Refereed)
    Abstract [en]

    N-myc belongs to the myc proto-oncogene family, which is involved in numerous cellular processes such as proliferation, growth, apoptosis, and differentiation. Conditional deletion of N-myc in the mouse nervous system disrupted brain development, indicating that N-myc plays an essential role during neural development. How the development of the olfactory epithelium and neurogenesis within are affected by the loss of N-myc has, however, not been determined. To address these issues, we examined an N-myc(Foxg1Cre) conditional mouse line, in which N-myc is depleted in the olfactory epithelium. First changes in N-myc mutants were detected at E11.5, with reduced proliferation and neurogenesis in a slightly smaller olfactory epithelium. The phenotype was more pronounced at E13.5, with a complete lack of Hes5-positive progenitor cells, decreased proliferation, and neurogenesis. In addition, stereological analyses revealed reduced cell size of post-mitotic neurons in the olfactory epithelium, which contributed to a smaller olfactory pit. Furthermore, we observed diminished proliferation and neurogenesis also in the vomeronasal organ, which likewise was reduced in size. In addition, the generation of gonadotropin-releasing hormone neurons was severely reduced in N-myc mutants. Thus, diminished neurogenesis and proliferation in combination with smaller neurons might explain the morphological defects in the N-myc depleted olfactory structures. Moreover, our results suggest an important role for N-myc in regulating ongoing neurogenesis, in part by maintaining the Hes5-positive progenitor pool. In summary, our results provide evidence that N-myc deficiency in the olfactory epithelium progressively diminishes proliferation and neurogenesis with negative consequences at structural and cellular levels. 

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