BMP signalling inhibits premature neural differentiation in the mouse embryo

Di-Gregorio, Aida; Sancho, Margarida; Stuckey, Daniel W.; Crompton, Lucy; Godwin, Jonathan; Mishina, Yuji; Rodríguez, Tristan A.

doi:10.1242/dev.005967

Cited by 156 publications

(179 citation statements)

References 78 publications

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“…The inhibition of BMP signaling seems revolutionarily conserved during the neural fate initiation in different organisms (9,13,52). Inhibition of the TGF␤ pathway has now been demonstrated to be sufficient to directly induce neural fate in mammalian embryos as well as pluripotent mouse and human embryonic stem cells (53), and consistently, our data also showed that the TGF␤ signaling has been inhibited during hESC neural differentiation processing (Fig.…”

Section: Discussionsupporting

confidence: 76%

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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Section: Discussionsupporting

confidence: 76%

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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“…These models have been questioned, based mostly on observations in the mouse system, in which signaling through BMP receptors appears to be required only for mesoderm induction and not for trophoblast lineage specification (23,46). The identification of BMP4-inducible p63, which is dispensable for mouse placentation (47), as an early marker of human proliferative CTB, may explain why BMP4 induces the TE lineage in hPSCs but appears not to be required for the same process in mice (46).…”

Section: Discussionmentioning

confidence: 99%

Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease

Horii

Wakeland

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

164

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Trophoblast is the primary epithelial cell type in the placenta, a transient organ required for proper fetal growth and development. Different trophoblast subtypes are responsible for gas/nutrient exchange (syncytiotrophoblasts, STBs) and invasion and maternal vascular remodeling (extravillous trophoblasts, EVTs). Studies of early human placental development are severely hampered by the lack of a representative trophoblast stem cell (TSC) model with the capacity for self-renewal and the ability to differentiate into both STBs and EVTs. Primary cytotrophoblasts (CTBs) isolated from early-gestation (6-8 wk) human placentas are bipotential, a phenotype that is lost with increasing gestational age. We have identified a CDX2 + /p63 + CTB subpopulation in the early postimplantation human placenta that is significantly reduced later in gestation. We describe a reproducible protocol, using defined medium containing bone morphogenetic protein 4 by which human pluripotent stem cells (hPSCs) can be differentiated into CDX2 + /p63 + CTB stem-like cells. These cells can be replated and further differentiated into STB-and EVT-like cells, based on marker expression, hormone secretion, and invasive ability. As in primary CTBs, differentiation of hPSC-derived CTBs in low oxygen leads to reduced human chorionic gonadotropin secretion and STB-associated gene expression, instead promoting differentiation into HLA-G + EVTs in an hypoxiainducible, factor-dependent manner. To validate further the utility of hPSC-derived CTBs, we demonstrated that differentiation of trisomy 21 (T21) hPSCs recapitulates the delayed CTB maturation and blunted STB differentiation seen in T21 placentae. Collectively, our data suggest that hPSCs are a valuable model of human placental development, enabling us to recapitulate processes that result in both normal and diseased pregnancies.human pluripotent stem cells | cytotrophoblast | extravillous trophoblast | syncytiotrophoblast | placenta

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“…It is also possible that AP2γ is concurrently regulated by other signals, such as FGF and Wnt [74]. BMP is proved to inhibit prematuration of neural tissues in the mouse embryo [12]. AP2γ might be the executor of BMP signaling in the nucleus to guarantee the normal progress of neural development by suppressing excessive cSox2 expansion in the young neural plate.…”

Section: Discussionmentioning

confidence: 99%

“…The "default model" proposes that BMP inhibits the "default" neural tendency of the ectodermal cells and induces them to adopt an epidermal fate, while BMP antagonists (noggin, chordin, and follistatin) from the organizer inhibit BMP signaling to protect the default neural fate [7,10,11]. The study in mouse embryo indicates that BMP signaling is required for inhibiting premature neural differentiation [12], and the involvement of Fgf and Wnt signaling pathways in neural induction has been established by the evidence from Xenopus and chick embryo [1,2,[13][14][15][16].…”

Section: Introductionmentioning

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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BMP signalling inhibits premature neural differentiation in the mouse embryo

Cited by 156 publications

References 78 publications

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

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

Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease

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

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