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Specification of dorsal telencephalic character by sequential Wnt and FGF signaling.
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
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2003 (English)In: Nature Neuroscience, ISSN 1097-6256, Vol. 6, no 7, 701-707 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2003. Vol. 6, no 7, 701-707 p.
Keyword [en]
Aging/genetics/metabolism, Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Morphogenetic Proteins/physiology, Cell Differentiation, Chick Embryo, Ectoderm/cytology/physiology, Embryonic Induction/*physiology, Epithelium, Eye Proteins, Fibroblast Growth Factors/classification/genetics/*physiology, Frizzled Receptors, Gene Expression Regulation; Developmental, Homeodomain Proteins/genetics/metabolism, Immunohistochemistry, In Situ Hybridization/methods, Mice, Nerve Tissue Proteins/genetics/metabolism, Organ Culture Techniques, Paired Box Transcription Factors, Proteins/physiology, Proto-Oncogene Proteins/genetics/*physiology, Pyrroles/pharmacology, Receptors; Fibroblast Growth Factor/physiology, Repressor Proteins, Signal Transduction/genetics/*physiology, Stem Cells/metabolism, Telencephalon/cytology/embryology/metabolism/*physiology, Transcription Factors, Wnt Proteins, Zebrafish Proteins
URN: urn:nbn:se:umu:diva-5932DOI: 10.1038/nn1068PubMedID: 12766771OAI: diva2:145600
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2009-11-25Bibliographically approved
In thesis
1. Specification of the lens and olfactory placodes and dorsoventral patterning of the telencephalon
Open this publication in new window or tab >>Specification of the lens and olfactory placodes and dorsoventral patterning of the telencephalon
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The vertebrate nervous system is a highly complex and intriguing structure with diverse functions. To understand the functional nervous system, we first have to be aware of how it is assembled during development. In this thesis the mechanism of early diversification and regionalisation necessary for subsequent formation of part of the nervous system, namely the telencephalon and the placodes, will be addressed. We have identified signalling molecules involved in the dorsoventral patterning of the telencephalon and we propose a mechanism for the induction and differential specification of the olfactory and lens placodes.

The telencephalon is regionalised along the dorsoventral axis during development. The cells situated dorsally will give rise to the cerebral cortex while the ventral and intermediate cells are mainly progenitors for the basal ganglia. The cerebral cortex is associated with higher cognitive functions whereas the basal ganglia control movements. We provide evidence that dorsal and intermediate telencephalic cells are re-specified from cells with an intrinsic ventral character. Dorsal telencephalic cells are specified at stage 10 in chick, while the intermediate cells are specified a few hours later, at stage 14. The expression of Wnt and Fibroblast growth factors (Fgfs) coincides with the time point when the dorsal cells are specified, and we provide evidence that Wnt and FGF signals act in a sequential way to specify dorsal telencephalic cells. The retinoic acid (RA) synthesising enzyme Raldh3 is expressed in proximity to the telencephalon, and our result suggests that RA is both required and sufficient to induce intermediate telencephalic cell types. Additionally, Fgf8 is expressed in the anterior neural ridge and the ventral telencephalic cells require FGF signals that oppose RA to maintain their character.

The olfactory and lens placodes contribute to the special sense organs associated with olfaction and vision, respectively. Olfactory and lens placodes are specified at gastrula stage in chick, and become spatially separated at the neural fold stage. We provide evidence that Bone morphogenetic protein (BMP) signalling is required for the induction of a pool of placodal progenitor cells. Furthermore, time of exposure to BMP signals plays a key role in the differential specification of the olfactory and lens placodes, where continued exposure to BMP signals promotes lens character at the expense of olfactory placodal cells.

Place, publisher, year, edition, pages
Umeå: Umeå centrum för molekylär medicin (UCMM), 2007. 77 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1119
telencephalon, olfactory, lens, BMP, RA, FGF, Wnt, development, placode, gradient, chick, nervous system, dorsoventral
Research subject
Developmental Neurosciences
urn:nbn:se:umu:diva-1347 (URN)978-91-7264-376-5 (ISBN)
Public defence
2007-10-05, Major Groove, 6L, NUS, Umeå, 13:00 (English)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2009-09-24Bibliographically approved
2. Specification of Dorsal and Intermediate Telencephalic Character
Open this publication in new window or tab >>Specification of Dorsal and Intermediate Telencephalic Character
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The telencephalon is the most highly evolved region of the vertebrate central nervous system (CNS). The major structures of the telencephalon - the cortex and basal ganglia – derive from the dorsally positioned pallium and the ventrally positioned subpallium, respectively. Differences in morphology, gene expression, and connectivity permit a subdivision of the developing telencephalon into domains that give rise to discrete regions of the adult brain. In mammals, the ventral region of the developing telencephalon can be subdivided into the medial (MGE) and lateral (LGE) ganglionic eminences. The dorsal midline cells give rise to the choroid plexus, and cells in the more lateral domain, the dorsal pallium, give rise to the cerebral cortex. Genetic studies have provided evidence that crossregulatory interactions between transcription factors contribute to the regionalization of the telencephalon. Less is known, however, about the secreted signals that induce the initial dorsoventral character of telencephalic cells.

Sonic hedgehog (SHH) is required for the specification of ventral character along the entire anteroposterior (AP) extent of the developing CNS, including the telencephalon. We show that WNT activity imposes an early generic dorsal telencephalic character and that Fibroblast Growth Factor (FGF) act sequentially, and in concert with WNT, to specify cells of definitive dorsal telencephalic character. We also show that retinoic acid (RA)-mediated signaling induces intermediate character in telencephalic cells, and that FGFs maintain cells of ventral character by opposing RA activity. The following model emerges from these findings. At gastrula stages, most or all prospective telencephalic cells become specified as ventral cells in response to node-derived SHH signals. At neural fold- and early neural plate stages, cells in the prospective dorsal and intermediate regions of the telencephalon cells are exposed to WNT signaling that induce a generic dorsal character. The head ectoderm adjacent to the telencephalon then starts to express the retinoic acid producing enzyme, Raldh3, thus exposing telencephalic cells to RA signals. At the same time prospective dorsal cells start to express WNT signals. RA signaling appears to promote the generation of intermediate/prestriatal cells, whereas WNT signal suppress the actions of RA on dorsal cells, which therefore maintain their dorsal character. From the neural plate stage, prospective ventral 6 telencephalic cells are exposed to FGF8 derived from the anterior neural ridge, and FGF8 maintains ventral telencephalic character by opposing the influence of RA signals in ventral cells. At early neural tube stages, the domain of Fgf8 expression expands dorsally and FGF signals derived from the dorsal midline region induce definitive dorsal/precortical cells. In the intermediate region of the telencephalon cells evade high levels of WNT and FGF signals, resulting in an environment in which RA signaling is able to induce prestriatal character.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2005. 77 p.
Molecular biology, telencephalon, forebrain, dorsoventral patterning, WNT, FGF, RA, retinoid-mediated signaling, development, specification, cortex, striatal, intermediate, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
urn:nbn:se:umu:diva-502 (URN)91-7305-860-2 (ISBN)
Public defence
2005-04-29, 10:00 (English)
Available from: 2005-04-19 Created: 2005-04-19 Last updated: 2009-09-24Bibliographically approved

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