Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis

Joksimovic, Milan; Yun, Beth; Raja, Kavitha; Anderegg, Angela; Chang, Wendy; Taketo, Makoto Mark; McKay, Ronald D.G.; Awatramani, Rajeshwar

doi:10.1038/nn.2243

Cited by 184 publications

(138 citation statements)

References 37 publications

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“…In particular, exposure to Wnt-1 resulted in a significant increase in the midbrain FP markers CORIN and NOV , as well as increases in the DA progenitor markers LMX1B, EN1 ,and NGN2 . These data are in agreement with previous studies showing that Wnt signaling is critical in the neurogenic response of the midbrain FP (Joksimovic et al, 2009). …”

Section: Resultssupporting

confidence: 94%

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RETRACTED: Efficient Derivation of Functional Floor Plate Tissue from Human Embryonic Stem Cells

et al. 2010

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The floor plate (FP) is a critical signaling center during neural development located along the ventral midline of the embryo. Little is known about human FP development due the lack of tissue accessibility. Here we report the efficient derivation of human embryonic stem cells (hESC−) derived FP tissue capable of secreting Netrin-1 and SHH and patterning primary and hESC derived tissues. FP induction in hESCs is dependent on early SHH exposure and occurs at the expense of anterior neurectoderm (AN). Global gene expression and functional studies identify SHH-mediated inhibition of DKK-1 as key factor in FP versus AN specification. hESC derived FP tissue is shown to be of anterior SIX6+ character but responsive to caudalizing factors suppressing SIX6 expression and inducing a shift in usage of region-specific SHH enhancers. These data define the early signals that drive human FP versus AN specification and determine regional identity in hESC derived FP.

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Section: Resultssupporting

confidence: 94%

“…The FP is generally considered a non-neurogenic region. However, genetic lineage mapping studies in the mouse have recently reported that the midbrain FP selectively exhibits neurogenic potential and is the source of ventral midbrain dopamine neurons (Kittappa et al, 2007; Ono et al, 2007; Joksimovic et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Efficient Derivation of Functional Floor Plate Tissue from Human Embryonic Stem Cells

et al. 2010

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“…In contrast, Wnt2(Ϫ/Ϫ) mice displayed a decrease in the proliferative capacity of DA progenitors in the ventricular zone of the VM and in their capacity to undergo neurogenesis, as indicated by the reduction of postmitotic cells (Nurr1 ϩ and TH ϩ cells) in the DA lineage. Wnt1 has also been described to regulate progenitor proliferation in the developing VM (17,19) as well as the number of Nurr1 and TH ϩ cells in the VM (16,18,19). However, other features of the Wnt1(Ϫ/Ϫ) mutant were not phenocopied by the Wnt2(Ϫ/Ϫ) animals, indicating that each Wnt regulates a specific combination of functions, some of which are redundantly regulated by distinct Wnts.…”

Section: Discussionmentioning

confidence: 99%

Wnt2 Regulates Progenitor Proliferation in the Developing Ventral Midbrain

Sousa

Villaescusa

Čajánek

et al. 2010

Journal of Biological Chemistry

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Wnts are secreted, lipidated proteins that regulate multiple aspects of brain development, including dopaminergic neuron development. In this study, we perform the first purification and signaling analysis of Wnt2 and define the function of Wnt2 in ventral midbrain precursor cultures, as well as in Wnt2-null mice in vivo. We found that purified Wnt2 induces the phosphorylation of both Lrp5/6 and Dvl-2/3, and activates ␤-catenin in SN4741 dopaminergic cells. Moreover, purified Wnt2 increases progenitor proliferation, and the number of dopaminergic neurons in ventral midbrain precursor cultures. In agreement with these findings, analysis of the ventral midbrain of developing Wnt2-null mice revealed a decrease in progenitor proliferation and neurogenesis that lead to a decrease in the number of postmitotic precursors and dopaminergic neurons. Collectively, our observations identify Wnt2 as a novel regulator of dopaminergic progenitors and dopaminergic neuron development.

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“…This development process is orchestrated by key signaling molecules [eg, sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), and Wnt signals] secreted from neighboring organizers and their downstream intrinsic transcription factors (eg, Otx2, Lmx1a/b, Foxa1/2, Ngn2, Pitx3, and Nurr1) [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Importantly, some of these transcription factors have been successfully exploited for enhancing the generation of mDA neurons by their overexpression in stem cells.…”

mentioning

confidence: 99%

Functional Roles of Nurr1, Pitx3, and Lmx1a in Neurogenesis and Phenotype Specification of Dopamine Neurons During In Vitro Differentiation of Embryonic Stem Cells

Hong

Chung

Leung

et al. 2014

Stem Cells and Development

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To elucidate detailed functional mechanisms of key fate-determining transcription factors (eg, Nurr1, Pitx3, and Lmx1a) and their functional interplay for midbrain dopamine (mDA) neurons, we developed highly efficient gain-of-function system by transducing the neural progenitors (NPs) derived from embryonic stem cells (ESCs) with retroviral vectors, allowing the analysis of downstream molecular and cellular effects. Overexpression of each factors, Nurr1, Pitx3, and Lmx1a robustly promoted the dopaminergic differentiation of ESC-NP cells exposed to sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8). In addition, each of these factors directly interacts with potential binding sites within the tyrosine hydroxylase (TH) gene and activated its promoter activity. Interestingly, however, overexpression of Nurr1, but not of Pitx3 or Lmx1a, generated a significant number of nonneuronal TH-positive cells. In line with this, Pitx3 and Lmx1a, but not Nurr1, induced expression of the Ngn2 gene, which is critical for neurogenesis. We also observed that Pitx3 directly bound to its potential binding sites within the Ngn2 gene and the pan-neuronal marker b-tubulin III gene, suggesting that Pitx3 contributes to mDA neurogenesis by directly regulating these genes. Taken together, our data demonstrate that key mDA regulators (Nurr1, Pitx3, and Lmx1a) play overlapping as well as distinct roles during neurogenesis and neurotransmitter phenotype determination of mDA neurons.

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Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis

Cited by 184 publications

References 37 publications

RETRACTED: Efficient Derivation of Functional Floor Plate Tissue from Human Embryonic Stem Cells

RETRACTED: Efficient Derivation of Functional Floor Plate Tissue from Human Embryonic Stem Cells

Wnt2 Regulates Progenitor Proliferation in the Developing Ventral Midbrain

Functional Roles of Nurr1, Pitx3, and Lmx1a in Neurogenesis and Phenotype Specification of Dopamine Neurons During In Vitro Differentiation of Embryonic Stem Cells

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