Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis, but results in vacillating dopamine progenitors

Navid Nouri, Meera J. Patel, Milan Joksimovic, Jean Francois Poulin, Angela Anderegg, M. Mark Taketo, Yong Chao Ma, Rajeshwar Awatramani

    Research output: Contribution to journalArticle

    12 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)131-142
    Number of pages12
    JournalMolecular and Cellular Neuroscience
    Volume68
    DOIs
    StatePublished - Sep 1 2015

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    Keywords

    • Floor plate
    • Lmx1b
    • Midbrain dopaminergic neurons
    • Wnt/beta-catenin

    ASJC Scopus subject areas

    • Molecular Biology
    • Cellular and Molecular Neuroscience
    • Cell Biology

    Cite this

    Nouri, N., Patel, M. J., Joksimovic, M., Poulin, J. F., Anderegg, A., Taketo, M. M., Ma, Y. C., & Awatramani, R. (2015). Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis, but results in vacillating dopamine progenitors. Molecular and Cellular Neuroscience, 68, 131-142. https://doi.org/10.1016/j.mcn.2015.07.002