Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Jones, Iwan
Publications (10 of 12) Show all publications
Nord, C., Jones, I., Garcia-Maestre, M., Hägglund, A.-C. & Carlsson, L. (2024). Reduced mTORC1-signaling in progenitor cells leads to retinal lamination deficits. Developmental Dynamics
Open this publication in new window or tab >>Reduced mTORC1-signaling in progenitor cells leads to retinal lamination deficits
Show others...
2024 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Neuronal lamination is a hallmark of the mammalian central nervous system (CNS) and underlies connectivity and function. Initial formation of this tissue architecture involves the integration of various signaling pathways that regulate the differentiation and migration of neural progenitor cells.

Results: Here, we demonstrate that mTORC1 mediates critical roles during neuronal lamination using the mouse retina as a model system. Down-regulation of mTORC1-signaling in retinal progenitor cells by conditional deletion of Rptor led to decreases in proliferation and increased apoptosis during embryogenesis. These developmental deficits preceded aberrant lamination in adult animals which was best exemplified by the fusion of the outer and inner nuclear layer and the absence of an outer plexiform layer. Moreover, ganglion cell axons originating from each Rptor-ablated retina appeared to segregate to an equal degree at the optic chiasm with both contralateral and ipsilateral projections displaying overlapping termination topographies within several retinorecipient nuclei. In combination, these visual pathway defects led to visually mediated behavioral deficits.

Conclusions: This study establishes a critical role for mTORC1-signaling during retinal lamination and demonstrates that this pathway regulates diverse developmental mechanisms involved in driving the stratified arrangement of neurons during CNS development.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
Chx10, dLGN, lamination, mTORC1, retina, Rptor
National Category
Neurosciences Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-223249 (URN)10.1002/dvdy.707 (DOI)001193263800001 ()38546215 (PubMedID)2-s2.0-85189534154 (Scopus ID)
Available from: 2024-04-18 Created: 2024-04-18 Last updated: 2024-04-18
Jones, I., Hägglund, A.-C. & Carlsson, L. (2022). Reduced mTORC1-signaling in retinal ganglion cells leads to vascular retinopathy. Developmental Dynamics, 251(2), 321-335
Open this publication in new window or tab >>Reduced mTORC1-signaling in retinal ganglion cells leads to vascular retinopathy
2022 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 251, no 2, p. 321-335Article in journal (Refereed) Published
Abstract [en]

Background: The coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in the mammalian retina where interneurons, astrocytes and retinal ganglion cells sculpt their vascular environment to meet the metabolic demands of visual function. Identifying the molecular networks that underlie neurovascular unit formation is an important step towards a deeper understanding of nervous system development and function.

Results: Here, we report that cell-to-cell mTORC1-signaling is essential for neurovascular unit formation during mouse retinal development. Using a conditional knockout approach we demonstrate that reduced mTORC1 activity in asymmetrically positioned retinal ganglion cells induces a delay in postnatal vascular network formation in addition to the production of rudimentary and tortuous vessel networks in adult animals. The severity of this vascular phenotype is directly correlated to the degree of mTORC1 down regulation within the neighboring retinal ganglion cell population.

Conclusions: This study establishes a cell nonautonomous role for mTORC1-signaling during retinal development. These findings contribute to our current understanding of neurovascular unit formation and demonstrate how ganglion cells actively sculpt their local environment to ensure that the retina is perfused with an appropriate supply of oxygen and nutrients.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
endothelial cells, mTORC1, Raptor, retinal ganglion cells, vascular retinopathy
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-185773 (URN)10.1002/dvdy.389 (DOI)000665814300001 ()34148274 (PubMedID)2-s2.0-85108777838 (Scopus ID)
Available from: 2021-07-05 Created: 2021-07-05 Last updated: 2024-04-18Bibliographically approved
Jones, I., Novikova, L. N., Wiberg, M., Carlsson, L. & Novikov, L. N. (2021). Human Embryonic Stem Cell-derived Neural Crest Cells Promote Sprouting and Motor Recovery Following Spinal Cord Injury in Adult Rats. Cell Transplantation, 30
Open this publication in new window or tab >>Human Embryonic Stem Cell-derived Neural Crest Cells Promote Sprouting and Motor Recovery Following Spinal Cord Injury in Adult Rats
Show others...
2021 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 30Article in journal (Refereed) Published
Abstract [en]

Spinal cord injury results in irreversible tissue damage and permanent sensorimotor impairment. The development of novel therapeutic strategies that improve the life quality of affected individuals is therefore of paramount importance. Cell transplantation is a promising approach for spinal cord injury treatment and the present study assesses the efficacy of human embryonic stem cell-derived neural crest cells as preclinical cell-based therapy candidates. The differentiated neural crest cells exhibited characteristic molecular signatures and produced a range of biologically active trophic factors that stimulated in vitro neurite outgrowth of rat primary dorsal root ganglia neurons. Transplantation of the neural crest cells into both acute and chronic rat cervical spinal cord injury models promoted remodeling of descending raphespinal projections and contributed to the partial recovery of forelimb motor function. The results achieved in this proof-of-concept study demonstrates that human embryonic stem cell-derived neural crest cells warrant further investigation as cell-based therapy candidates for the treatment of spinal cord injury.

Place, publisher, year, edition, pages
Sage Publications, 2021
Keywords
hESCs, motor recovery, neural crest cells, spinal cord injury, transplantation, vertical cylinder test
National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:umu:diva-180766 (URN)10.1177/0963689720988245 (DOI)000617264000001 ()33522309 (PubMedID)2-s2.0-85100676539 (Scopus ID)
Available from: 2021-02-25 Created: 2021-02-25 Last updated: 2024-04-18Bibliographically approved
Jones, I., Hägglund, A.-C. & Carlsson, L. (2019). Reduced mTORC1-signalling in retinal progenitor cells leads to visual pathway dysfunction. Biology Open, 8(8), Article ID bio044370.
Open this publication in new window or tab >>Reduced mTORC1-signalling in retinal progenitor cells leads to visual pathway dysfunction
2019 (English)In: Biology Open, ISSN 2046-6390, Vol. 8, no 8, article id bio044370Article in journal (Refereed) Published
Abstract [en]

Development of the vertebrate central nervous system involves the co-ordinated differentiation of progenitor cells and the establishment of functional neural networks. This neurogenic process is driven by both intracellular and extracellular cues that converge on the mammalian target of rapamycin complex 1 (mTORC1). Here we demonstrate that mTORC1-signalling mediates multi-faceted roles during central nervous system development using the mouse retina as a model system. Downregulation of mTORC1-signalling in retinal progenitor cells by conditional ablation of Rptor leads to proliferation deficits and an over-production of retinal ganglion cells during embryonic development. In contrast, reduced mTORC1-signalling in postnatal animals leads to temporal deviations in programmed cell death and the consequent production of asymmetric retinal ganglion cell mosaics and associated loss of axonal termination topographies in the dorsal lateral geniculate nucleus of adult mice. In combination these developmental defects induce visually mediated behavioural deficits. These collective observations demonstrate that mTORC1-signalling mediates critical roles during visual pathway development and function.

Place, publisher, year, edition, pages
The Company of Biologists, 2019
Keywords
Raptor, mTORC1, Retina, RGCs, dLGN, Visual cliff test
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-164651 (URN)10.1242/bio.044370 (DOI)000484809100019 ()31285269 (PubMedID)2-s2.0-85072065895 (Scopus ID)
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2024-04-18Bibliographically approved
Jones, I., Yelhekar, T. D., Wiberg, R., Kingham, P. J., Johansson, S., Wiberg, M. & Carlsson, L. (2018). Development and validation of an in vitro model system to study peripheral sensory neuron development and injury. Scientific Reports, 8, Article ID 15961.
Open this publication in new window or tab >>Development and validation of an in vitro model system to study peripheral sensory neuron development and injury
Show others...
2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 15961Article in journal (Refereed) Published
Abstract [en]

The ability to discriminate between diverse types of sensation is mediated by heterogeneous populations of peripheral sensory neurons. Human peripheral sensory neurons are inaccessible for research and efforts to study their development and disease have been hampered by the availability of relevant model systems. The in vitro differentiation of peripheral sensory neurons from human embryonic stem cells therefore provides an attractive alternative since an unlimited source of biological material can be generated for studies that specifically address development and injury. The work presented in this study describes the derivation of peripheral sensory neurons from human embryonic stem cells using small molecule inhibitors. The differentiated neurons express canonical- and modality-specific peripheral sensory neuron markers with subsets exhibiting functional properties of human nociceptive neurons that include tetrodotoxin-resistant sodium currents and repetitive action potentials. Moreover, the derived cells associate with human donor Schwann cells and can be used as a model system to investigate the molecular mechanisms underlying neuronal death following peripheral nerve injury. The quick and efficient derivation of genetically diverse peripheral sensory neurons from human embryonic stem cells offers unlimited access to these specialised cell types and provides an invaluable in vitro model system for future studies.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-153701 (URN)10.1038/s41598-018-34280-3 (DOI)000448589200037 ()30374154 (PubMedID)2-s2.0-85055617140 (Scopus ID)
Funder
Swedish Research Council, 22292Gunvor och Josef Anérs stiftelseVästerbotten County Council
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2024-04-18Bibliographically approved
Jones, I., Novikova, L. N., Novikov, L. N., Renardy, M., Ullrich, A., Wiberg, M., . . . Kingham, P. J. (2018). Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury. Journal of Tissue Engineering and Regenerative Medicine, 12(4), E2099-E2109
Open this publication in new window or tab >>Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury
Show others...
2018 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 12, no 4, p. E2099-E2109Article in journal (Refereed) Published
Abstract [en]

Surgical intervention is the current gold standard treatment following peripheral nerve injury. However, this approach has limitations, and full recovery of both motor and sensory modalities often remains incomplete. The development of artificial nerve grafts that either complement or replace current surgical procedures is therefore of paramount importance. An essential component of artificial grafts is biodegradable conduits and transplanted cells that provide trophic support during the regenerative process. Neural crest cells are promising support cell candidates because they are the parent population to many peripheral nervous system lineages. In this study, neural crest cells were differentiated from human embryonic stem cells. The differentiated cells exhibited typical stellate morphology and protein expression signatures that were comparable with native neural crest. Conditioned media harvested from the differentiated cells contained a range of biologically active trophic factors and was able to stimulate in vitro neurite outgrowth. Differentiated neural crest cells were seeded into a biodegradable nerve conduit, and their regeneration potential was assessed in a rat sciatic nerve injury model. A robust regeneration front was observed across the entire width of the conduit seeded with the differentiated neural crest cells. Moreover, the up-regulation of several regeneration-related genes was observed within the dorsal root ganglion and spinal cord segments harvested from transplanted animals. Our results demonstrate that the differentiated neural crest cells are biologically active and provide trophic support to stimulate peripheral nerve regeneration. Differentiated neural crest cells are therefore promising supporting cell candidates to aid in peripheral nerve repair.

Keywords
artificial nerve graft, human embryonic stem cells, neural crest cells, peripheral nerve injuries, ripheral nervous system, VELOPMENTAL EVOLUTION, V314B, P95 e Gabsang, 2007, NATURE BIOTECHNOLOGY, V25, P1468
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-147466 (URN)10.1002/term.2642 (DOI)000430395400024 ()29327452 (PubMedID)2-s2.0-85043468899 (Scopus ID)
Funder
Swedish Research Council, 2014-2306
Available from: 2018-05-28 Created: 2018-05-28 Last updated: 2024-04-18Bibliographically approved
Hagglund, A.-C., Jones, I. & Carlsson, L. (2017). A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development. Disease Models and Mechanisms, 10(3), 245-257
Open this publication in new window or tab >>A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development
2017 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 10, no 3, p. 245-257Article in journal (Refereed) Published
Abstract [en]

Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

Keywords
Tsc1, mTORC1, Pax6, Ciliary body, Iris, Anterior segment dysgenesis
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-133816 (URN)10.1242/dmm.028605 (DOI)000395717100005 ()28250050 (PubMedID)2-s2.0-85018362666 (Scopus ID)
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2024-04-18Bibliographically approved
Jones, I., Hägglund, A.-C., Törnqvist, G., Nord, C., Ahlgren, U. & Carlsson, L. (2015). A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development. Disease Models and Mechanisms, 8(12), 1517-1529
Open this publication in new window or tab >>A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development
Show others...
2015 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, no 12, p. 1517-1529Article in journal (Refereed) Published
Abstract [en]

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-120197 (URN)10.1242/dmm.021972 (DOI)000368905300004 ()26449264 (PubMedID)2-s2.0-84952767120 (Scopus ID)
Available from: 2016-05-11 Created: 2016-05-11 Last updated: 2024-04-18Bibliographically approved
Svenningsson, A., Dring, A. M., Fogdell-Hahn, A., Jones, I., Engdahl, E., Lundkvist, M., . . . Gilthorpe, J. D. (2013). Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies. Neurology, 80(10), 965-967
Open this publication in new window or tab >>Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies
Show others...
2013 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 80, no 10, p. 965-967Article in journal, Editorial material (Other academic) Published
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-67965 (URN)10.1212/WNL.0b013e3182840be3 (DOI)000315773500022 ()2-s2.0-84876251384 (Scopus ID)
Available from: 2013-04-11 Created: 2013-04-09 Last updated: 2024-04-18Bibliographically approved
von Hofsten, J., Karlsson, J., Jones, I. & Olsson, P.-E. (2002). Expression and Regulation of Fushi Tarazu Factor-1 and Steroidogenic Genes During Reproduction in Arctic Char (Salvelinus alpinus). Biology of Reproduction, 67(4), 1297-1304
Open this publication in new window or tab >>Expression and Regulation of Fushi Tarazu Factor-1 and Steroidogenic Genes During Reproduction in Arctic Char (Salvelinus alpinus)
2002 (English)In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 67, no 4, p. 1297-1304Article in journal (Refereed) Published
Abstract [en]

Teleost fushi tarazu factor-1 (FTZ-F1) is a potential regulator of steroidogenesis. The present study shows sex-specific regulation of Arctic char fushi tarazu factor-1 (acFF1) and steroidogenic genes during reproductive maturation and in response to hormone treatment. A link between gonadal expression of acFF1, steroidogenic acute regulatory protein (StAR), and cytochrome P450-11A (CYP11A), was observed in the reproductive maturation process, as elevated acFF1 mRNA and protein levels preceded increased StAR and CYP11A transcription. Sex-specific differences were observed as estrogen treatment resulted in down-regulated levels of acFF1 mRNA in testis and male head kidney, whereas no significant effect was observed in females. 11-Ketotestosterone (11-KT) down-regulated CYP11A and 3beta-hydroxysteroid dehydrogenase (3betaHSD) in head kidney and up-regulated CYP11A in testis. StAR remained unaffected by hormone treatment. This suggests that acFF1 is controlled by 17beta-estradiol, whereas the effects on CYP11A and 3betaHSD are mediated by 11-KT. Coexpression of acFF1, StAR, and CYP11A was observed in head kidney, in addition to gonads, indicating correlation between these steroidogenic genes. StAR and acFF1 were also coexpressed in liver, suggesting a potential role in cholesterol metabolism. Although these results indicate conserved steroidogenic functions for FTZ-F1 among vertebrates, they also raise the question of additional roles for FTZ-F1 in teleosts.

Place, publisher, year, edition, pages
Society for the Study of Reproduction, 2002
Keywords
gene regulation, seasonal reproduction, steroid hormones
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-4279 (URN)10.1095/biolreprod.102.005181 (DOI)000178266200033 ()12297548 (PubMedID)
Available from: 2004-11-19 Created: 2004-11-19 Last updated: 2024-04-18Bibliographically approved
Organisations

Search in DiVA

Show all publications