Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo

Cajal, Marieke; Lawson, Kirstie A.; Hill, Bill; Moreau, Anne; Rao, Jianguo; Ross, Allyson; Collignon, Jérôme; Camus, Anne

doi:10.1242/dev.075499

Cited by 63 publications

(64 citation statements)

References 76 publications

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“…8D, Fig. S5) (Cajal et al, 2012). Dlx5 expression was confined to the proximal ectoderm in E7.5 control and N1ICD epi embryos (n=5/6; Fig.…”

Section: Notch Activation Induces Neural Specificationmentioning

confidence: 87%

“…In order to investigate whether the NOTCH pathway can also play such an early role during in vivo neural development, we analysed the formation of neurectodermal tissue in N1ICD epi embryos. The transcription factor SOX1 is first expressed in the anterior region fated to become neurectoderm when the neural plate forms at E7.5 (Cajal et al, 2012;Pevny et al, 1998). Strikingly, we found that in N1ICD epi embryos Sox1 was expressed in an anterior distal domain at a time when Sox1 transcripts could not yet be detected in control littermates (n=10/11; Fig.…”

Section: Notch Activation Induces Neural Specificationmentioning

confidence: 99%

“…At E7.5, the transcription factors coding genes Otx2, Hesx1 and Six3 are expressed in overlapping domains of the anterior surface ectoderm and anterior neural plate (Cajal et al, 2012). After gastrulation, their expression is found in the forebrain, with Otx2 being also expressed in the midbrain (Oliver et al, 1995;Simeone et al, 1993;Thomas and Beddington, 1996).…”

Section: Notch Activation Perturbs Anterior Ectoderm Formationmentioning

confidence: 99%

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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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“…8D, Fig. S5) (Cajal et al, 2012). Dlx5 expression was confined to the proximal ectoderm in E7.5 control and N1ICD epi embryos (n=5/6; Fig.…”

Section: Notch Activation Induces Neural Specificationmentioning

confidence: 87%

Section: Notch Activation Induces Neural Specificationmentioning

confidence: 99%

Section: Notch Activation Perturbs Anterior Ectoderm Formationmentioning

confidence: 99%

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

et al. 2015

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“…Detailed spatiotemporal expression analysis showed that AP2γ is expressed in the entire epiblast before HH stage 3 and gradually shifts outwards to the putative epidermal ectoderm at HH stage 4, accompanying with comple- mentary cSox2 expansion. Similarly, mouse AP2γ might have expression changes from ICM at E3.5 [47] to nonneural ectoderm at the late gastrulation stage [48]. The dynamic expression pattern of cAP2γ suggests that AP2γ might play multiple roles in ectodermal patterning in different regions of the epiblast.…”

Section: Discussionmentioning

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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“…In mouse early embryo development, the neural fate commitment occurs during gastrulation, and a portion of anterior ectoderm is specified to adopt the neural fate (28,29). One of our previous studies documented the spatial transcriptome of the epiblast at the mid-gastrulation (E7.0) (29).…”

Section: Comparative Analysis Validates Module 3 Associated Day 8/10 mentioning

confidence: 99%

Transcriptome analysis reveals determinant stages controlling human embryonic stem cell commitment to neuronal cells

Wang

Qiao³

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangProper neural commitment is essential for ensuring the appropriate development of the human brain and for preventing neurodevelopmental diseases such as autism spectrum disorders, schizophrenia, and intellectual disorders. However, the molecular mechanisms underlying the neural commitment in humans remain elusive. Here, we report the establishment of a neural differentiation system based on human embryonic stem cells (hESCs) and on comprehensive RNA sequencing analysis of transcriptome dynamics during early hESC differentiation. Using weighted gene co-expression network analysis, we reveal that the hESC neurodevelopmental trajectory has five stages: pluripotency (day 0); differentiation initiation (days 2, 4, and 6); neural commitment (days 8 -10); neural progenitor cell proliferation (days 12, 14, and 16); and neuronal differentiation (days 18, 20, and 22). These stages were characterized by unique module genes, which may recapitulate the early human cortical development. Moreover, a comparison of our RNA-sequencing data with several other transcriptome profiling datasets from mice and humans indicated that Module 3 associated with the day 8 -10 stage is a critical window of fate switch from the pluripotency to the neural lineage. Interestingly, at this stage, no key extrinsic signals were activated. In contrast, using CRISPR/ Cas9 -mediated gene knockouts, we also found that intrinsic hub transcription factors, including the schizophrenia-associated SIX3 gene and septo-optic dysplasia-related HESX1 gene, are required to program hESC neural determination. Our results improve the understanding of the mechanism of neural commitment in the human brain and may help elucidate the etiology of human mental disorders and advance therapies for managing these conditions. Brain development is one of the most complicated and hierarchical events in mammals. A series of temporal processes, including neural commitment, patterning and sub-regionalization, neurogenesis, and neuronal network formation, are required to generate a functional brain (1-4). Defects in any of these processes will lead to neurodevelopmental diseases such as autism spectrum disorders, schizophrenia, depression, and epilepsy. Neural commitment occurs after gastrulation and initiates the program to form neural epithelium (5-7). Many studies on amphibians and rodents reveal that the inhibition of BMP 3 signaling is an evolutionally conserved mechanism for neural induction; in addition, intrinsic factors play pivotal roles to direct fate transition from pluripotency to neural lineage (8 -11). Nonetheless, how the neural commitment is ensured in human brain has not been clearly elucidated. Systematically understanding the critical role of signaling pathways and transcriptional factors in modulating and shaping human brain development is hindered by limited accessibility to early embryos and inadequate amounts of stage-specific and cell type-specific materials. These problems may now be solved by the use of human embryonic stem cells (h...

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Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo

Cited by 63 publications

References 76 publications

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

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

Transcriptome analysis reveals determinant stages controlling human embryonic stem cell commitment to neuronal cells

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