title: Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis, but results in vacillating dopamine progenitors.
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.
authors.affiliation: Northwestern University, Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg., 303 E Superior Street, Chicago, IL 60611, USA. Electronic address: navidnouri2015@u.northwestern.edu.
authors.forename: Navid
authors.initials: N
authors.lastname: Nouri
authors.affiliation: Northwestern University, Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg., 303 E Superior Street, Chicago, IL 60611, USA; Committee on Neurobiology, University of Chicago, 924 E 57th St. R222, Chicago, IL 60637, USA. Electronic address: meerapatel@uchicago.edu.
authors.forename: Meera J
authors.initials: MJ
authors.lastname: Patel
authors.affiliation: Northwestern University, Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg., 303 E Superior Street, Chicago, IL 60611, USA. Electronic address: milanjok@hotmail.com.
authors.forename: Milan
authors.initials: M
authors.lastname: Joksimovic
authors.affiliation: Northwestern University, Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg., 303 E Superior Street, Chicago, IL 60611, USA. Electronic address: j-poulin@northwestern.edu.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Poulin
authors.affiliation: Northwestern University, Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg., 303 E Superior Street, Chicago, IL 60611, USA. Electronic address: angela.anderegg@gmail.com.
authors.forename: Angela
authors.initials: A
authors.lastname: Anderegg
authors.affiliation: Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo, Kyoto 606-8501, Japan. Electronic address: taketo@mfour.med.kyoto-u.ac.jp.
authors.forename: M Mark
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Children's Hospital of Chicago Research Center, 2430 North Halsted Street, Room C321, Chicago, IL 60614, USA. Electronic address: ma@northwestern.edu.
authors.forename: Yong-Chao
authors.initials: YC
authors.lastname: Ma
authors.affiliation: Northwestern University, Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg., 303 E Superior Street, Chicago, IL 60611, USA. Electronic address: r-awatramani@northwestern.edu.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Awatramani
mesh_terms: D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004298:Dopamine; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D022661:RNA, Untranslated; D014446:Tyrosine 3-Monooxygenase; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C465570:Shh protein, mouse; C486336:Neurog1 protein, mouse
keywords: Floor plate; Lmx1b; Midbrain dopaminergic neurons; Wnt/beta-catenin