Directed differentiation of telencephalic precursors from embryonic stem cells

Watanabe, Kiichi; Kamiya, Daisuke; Nishiyama, Ayaka; Katayama, T; Nozaki, Satoshi; Kawasaki, Hiroshi; Watanabe, Yasuyoshi; Mizuseki, Kenji; Sasai, Yoshiki

doi:10.1038/nn1402

Cited by 720 publications

(679 citation statements)

References 47 publications

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“…Consistently, BMP signaling inhibits neural induction and stimulates the formation of the epidermis from mouse ES cells [62][63][64]. Moreover, activation of Nodal signals suppresses neural differentiation from mouse ES cells [65]. Together, these findings indicate that TGF-β family signaling inhibits the commitment of ES cells to neuroectoderm.…”

Section: Ectoderm Derivativesmentioning

confidence: 78%

Roles of TGF-β family signaling in stem cell renewal and differentiation

2008

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Section: Ectoderm Derivativesmentioning

confidence: 78%

Roles of TGF-β family signaling in stem cell renewal and differentiation

2008

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“…The identification of the regulatory networks controlling these sequential events has recently benefited from studies highlighting the similarities between the precursors present in the embryo and the in vitro cell types obtained in neural differentiation protocols of stem cells (IwafuchiDoi et al, 2012;Lupo et al, 2014). In vivo and in vitro evidence has demonstrated that inhibition of NODAL/ACTIVIN signalling promotes neural fate acquisition in the mouse embryo, as well as during differentiation of mESCs, mouse epiblast stem cells (mEpiSC), and hESCs (Camus et al, 2006;Chng et al, 2010;Li et al, 2013;Patani et al, 2009;Smith et al, 2008;Turner et al, 2014;Vallier et al, 2009;Watanabe et al, 2005). It is tempting to extrapolate that the attenuation of NODAL signalling observed in N1ICD epi embryos from E6.5 contributes to the premature expression of Sox1 in the distal anterior epiblast of these embryos.…”

Section: Discussionmentioning

confidence: 99%

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

et al. 2015

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NOTCH signalling is an evolutionarily conserved pathway involved in intercellular communication essential for cell fate choices during development. Although dispensable for early aspects of mouse development, canonical RBPJ-dependent NOTCH signalling has been shown to influence lineage commitment during embryonic stem cell (ESC) differentiation. NOTCH activation in ESCs promotes the acquisition of a neural fate, whereas its suppression favours their differentiation into cardiomyocytes. This suggests that NOTCH signalling is implicated in the acquisition of distinct embryonic fates at early stages of mammalian development. In order to investigate in vivo such a role for NOTCH signalling in shaping cell fate specification, we use genetic approaches to constitutively activate the NOTCH pathway in the mouse embryo. Early embryonic development, including the establishment of anterior-posterior polarity, is not perturbed by forced NOTCH activation. By contrast, widespread NOTCH activity in the epiblast triggers dramatic gastrulation defects. These are fully rescued in a RBPJ-deficient background. Epiblast-specific NOTCH activation induces acquisition of neurectoderm identity and disrupts the formation of specific mesodermal precursors including the derivatives of the anterior primitive streak, the mouse organiser. In addition, we show that forced NOTCH activation results in misregulation of NODAL signalling, a major determinant of early embryonic patterning. Our study reveals a previously unidentified role for canonical NOTCH signalling during mammalian gastrulation. It also exemplifies how in vivo studies can shed light on the mechanisms underlying cell fate specification during in vitro directed differentiation.

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“…Within the differentially expressed genes, AP2γ was found to be markedly upregulated by BMP4 at both mRNA and protein levels (Supplementary information, Figure S1). ESC neural differentiation in knockout serum replacement (KSR) medium was used as an in vitro model [38,39] to study AP2γ function in early embryonic development. We found that AP2γ mRNA was expressed in undifferentiated mouse ESCs and that its level gradually decreased with progressing neural conversion ( Figure 1A), suggesting that AP2γ might be involved in the neural differentiation of ESCs.…”

Section: Ap2γ Knockdown Facilitates Neural Differentiation and Impairmentioning

confidence: 99%

AP2γ regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning

et al. 2012

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Bone morphogenetic protein (BMP) inhibits neural specification and induces epidermal differentiation during ectodermal patterning. However, the mechanism of this process is not well understood. Here we show that AP2γ, a transcription factor activator protein (AP)-2 family member, is upregulated by BMP4 during neural differentiation of pluripotent stem cells. Knockdown of AP2γ facilitates mouse embryonic stem cell (ESC) neural fate determination and impairs epidermal differentiation, whereas AP2γ overexpression inhibits neural conversion and promotes epidermal commitment. In the early chick embryo, AP2γ is expressed in the entire epiblast before HH stage 3 and gradually shifts to the putative epidermal ectoderm during HH stage 4. In the future neural plate AP2γ inhibits excessive neural expansion and it also promotes epidermal development in the surface ectoderm. Moreover, AP2γ knockdown in ESCs and chick embryos partially rescued the neural inhibition and epidermal induction effects of BMP4. Mechanistic studies showed that BMP4 directly regulates AP2γ expression through Smad1 binding to the AP2γ promoter. Taken together, we propose that during the early stages of ectodermal patterning in the chick embryo, AP2γ acts downstream of the BMP pathway to restrict precocious neural expansion in the prospective neural plate and initiates epidermal differentiation in the future epidermal ectoderm.

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Directed differentiation of telencephalic precursors from embryonic stem cells

Cited by 720 publications

References 47 publications

Roles of TGF-β family signaling in stem cell renewal and differentiation

Roles of TGF-β family signaling in stem cell renewal and differentiation

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

AP2γ regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning

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