Dataset Information

Dissecting the role of Wnt signaling and its interactions with FGF signaling during midbrain neurogenesis.

ABSTRACT: Interactions between FGF and Wnt/ bcat signaling control development of the midbrain. The nature of this interaction and how these regulate patterning, growth and differentiation is less clear, as it has not been possible to temporally dissect the effects of one pathway relative to the other. We have employed pharmacological and genetic tools to probe the temporal and spatial roles of FGF and Wnt in controlling the specification of early midbrain neurons. We identify a ?-catenin (bcat) independent role for GSK-3 in modulating FGF activity and hence neuronal patterning. This function is complicated by an overlap with bcat-dependent regulation of FGF signaling, through the regulation of sprouty4. Additionally we reveal how attenuation of Axin protein function can promote fluctuating levels of bcat activity that are dependent on FGF activity. This highlights the complex nature of the interactions between FGF and Wnt/ bcat and reveals that they act at multiple levels to control each others activity in the midbrain.

SUBMITTER: Dyer C

PROVIDER: S-EPMC4973611 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Dissecting the role of Wnt signaling and its interactions with FGF signaling during midbrain neurogenesis.

Dyer Carlene C Blanc Eric E Stanley Rob J RJ Knight Robert D RD

Neurogenesis (Austin, Tex.) 20150921 1

Interactions between FGF and Wnt/ bcat signaling control development of the midbrain. The nature of this interaction and how these regulate patterning, growth and differentiation is less clear, as it has not been possible to temporally dissect the effects of one pathway relative to the other. We have employed pharmacological and genetic tools to probe the temporal and spatial roles of FGF and Wnt in controlling the specification of early midbrain neurons. We identify a β-catenin (bcat) independe ...[more]

PMID: 27606327

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Project description:The floor plate (FP), a ventral midline structure of the developing neural tube, has differential neurogenic capabilities along the anterior-posterior axis. The midbrain FP, unlike the hindbrain and spinal cord floor plate, is highly neurogenic and produces midbrain dopaminergic (mDA) neurons. Canonical Wnt/beta-catenin signaling, at least in part, is thought to account for the difference in neurogenic capability. Removal of beta-catenin results in mDA progenitor specification defects as well as a profound reduction of neurogenesis. To examine the effects of excessive Wnt/beta-catenin signaling on mDA specification and neurogenesis, we have analyzed a model wherein beta-catenin is conditionally stabilized in the Shh+domain. Here, we show that the Foxa2+/Lmx1a+ domain is extended rostrally in mutant embryos, suggesting that canonical Wnt/beta-catenin signaling can drive FP expansion along the rostrocaudal axis. Although excess canonical Wnt/beta-catenin signaling generally promotes neurogenesis at midbrain levels, less tyrosine hydroxylase (Th)+, mDA neurons are generated, particularly impacting the Substantia Nigra pars compacta. This is likely because of improper progenitor specification. Excess canonical Wnt/beta-catenin signaling causes downregulation of net Lmx1b, Shh and Foxa2 levels in mDA progenitors. Moreover, these progenitors assume a mixed identity to that of Lmx1a+/Lmx1b+/Nkx6-1+/Neurog1+ progenitors. We also show by lineage tracing analysis that normally, Neurog1+ progenitors predominantly give rise to Pou4f1+ neurons, but not Th+ neurons. Accordingly, in the mutant embryos, Neurog1+ progenitors at the midline generate ectopic Pou4f1+ neurons at the expense of Th+ mDA neurons. Our study suggests that an optimal dose of Wnt/beta-catenin signaling is critical for proper establishment of the mDA progenitor character. Our findings will impact embryonic stem cell protocols that utilize Wnt pathway reagents to derive mDA neuron models and therapeutics for Parkinson's disease.

Dataset Information

Dissecting the role of Wnt signaling and its interactions with FGF signaling during midbrain neurogenesis.

Publications

Dissecting the role of Wnt signaling and its interactions with FGF signaling during midbrain neurogenesis.

Similar Datasets

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