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SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

ABSTRACT: Generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in human embryos is poorly understood. Here, we report that transcription factor SOX21 is required for telencephalic fate specification from hESCs. SOX21 knockout (KO) impairs telencephalic fate specification, concomitant with the activation of diencephalic genes and Wnt signaling. Inhibition of Wnt signaling restores telencephalic specification from SOX21 KO hESCs. Analysis of global SOX21 DNA binding profiles and SOX21-regulated genes identifies SOX21 targets. SOX21 interacts with b-catenin and interferes with TCF4/b-catenin binding to the enhancer of WNT8B. Double KO of SOX21 and WNT8B restores telencephalic specification, indicating that SOX21 specifies the telencephalic fate through repressing WNT8B expression. Moreover, the high and low levels of SOX21 in the telencephalon and diencephalon, respectively, in developing human brains support its role in telencephalic fate specification. Collectively, this study unveils previously unappreciated roles of SOX21 and sheds light on the transcriptional control of telencephalic patterning in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110504 | GEO | 2019/10/28

REPOSITORIES: GEO

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SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

Project description:Generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in human embryos is poorly understood. Here, we report that transcription factor SOX21 is required for telencephalic fate specification from hESCs. SOX21 knockout (KO) impairs telencephalic fate specification, concomitant with the activation of diencephalic genes and Wnt signaling. Inhibition of Wnt signaling restores telencephalic specification from SOX21 KO hESCs. Analysis of global SOX21 DNA binding profiles and SOX21-regulated genes identifies SOX21 targets. SOX21 interacts with b-catenin and interferes with TCF4/b-catenin binding to the enhancer of WNT8B. Double KO of SOX21 and WNT8B restores telencephalic specification, indicating that SOX21 specifies the telencephalic fate through repressing WNT8B expression. Moreover, the high and low levels of SOX21 in the telencephalon and diencephalon, respectively, in developing human brains support its role in telencephalic fate specification. Collectively, this study unveils previously unappreciated roles of SOX21 and sheds light on the transcriptional control of telencephalic patterning in humans.

2019-10-28 | GSE138094 | GEO

Genome-wide map of SOX21 occupancy in human embryonic stem cell-derived neural progenitor cells [ChIP-seq]

Project description:To understand how SOX21 regulates neural fate specification, we differentiated wild type and SOX21 knockout hESC into neural epithelial cells (NECs) using dual SMAD inhibition protocol. We collected cells at neural differentiation day 5 and performed SOX21 ChIP-seq to investigate the genome-wide binding profiles. Meanwhile, we also carried out b-catenin ChIP-seq in wild type and SOX21 knockout NECs to dissect the role of SOX21 in Wnt signaling inhibition, thus providing important information for the mechanism underlying SOX21's functions in early neural fate specification.

2019-10-28 | GSE110505 | GEO

Gene analysis of ameloblasts in Sox21KO

Project description:Tooth and hair development starts from ectodermal invaginations. However, the determination of organ-specific cell fates is poorly understood. The transcription factor Sox21 is expressed in the epithelium of developing teeth. We discovered that disruption of Sox21 caused severe enamel hypoplasia and ectopic hair formation in the gingiva in Sox21 knockout incisors. We dissected tooth germ from P1 Sox21 KO and control incisors for microarray. In particular, several markers of ameloblast maturity, i.e. amelotin (Amtn), laminin α3 (Lama3), and kallikrein-related peptidase 4 (Klk4), were included among the downregulated molecules in Sox21 KO tooth germ, whereas the expression of Mmp20 and Amel was not changed. On the other hand, numerous keratin-related genes were upregulated in the Sox21 KO tooth germ and WT skin. As in the microarray results, the expression of dental epithelial stem cell marker Sox2, as well as keratin family and hair-related genes such as Lgr5, were increased in Sox21 KO dental epithelium. Taken together, these results reflected the perturbed differentiation of ameloblasts and a cell fate change in the Sox21 KO incisors.

2020-01-01 | GSE99359 | GEO

Role of ASCL1 in human neural development

Project description:As a proneural gene, ASCL1 was reported to be important to neurogenesis. To better illustrate the role of ASCL1 in human telencephalon development, we genetically engineered an ASCL1 knockout (KO) hESC line and ASCL1 rescue (RE) hESC line, and then preformed RNA sequencing when WT, KO and RE were differentiated into neural progenitors in vitro. Our results showed that ASCL1 KO hESCs could be regularly maintained in vitro, and could be efficiently specified into neuroectoderm cells and following telencephalic neural progenitors. Remarkably, dorsal progenitors-derived from ASCL1 KO hESCs failed to differentiate into DCX positive neuroblasts. In addition, dorsal and ventral progenitors retained higher expression of VZ/ESVZ genes but had much lower expression of LSVZ genes after KO of ASCL1. Re-introducing of ASCL1 in KO hESCs through a doxycycline (Dox) inducible overexpression system reversed the gene expression changes induced by cortical progenitors with ASCL1 KO. Taken all these together, our results revealed a pivotal role of ASCL1 in both dorsal and ventral telencephalic development by progressing the cycling progenitors within the ESVZ to post-mitotic early born neurons in the LSVZ in human telencephalon.

2022-12-21 | GSE149096 | GEO

Gene expression profiling reveals a novel regulatory role for Sox21 in mouse trophoblast stem cell differentiation.

2015-11-10 | GSE67037 | GEO

SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

Project description:SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

| PRJNA433872 | ENA

SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

Project description:SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

| PRJNA433877 | ENA

SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

Project description:SOX21 ensures rostral forebrain identity by suppression of WNT8B during neural regionalization of human embryonic stem cells

| PRJNA574589 | ENA

Gene expression profiling reveals a novel regulatory role for Sox21 in mouse trophoblast stem cell differentiation.

Project description:In this study we introduced Sox21 as a new regulator of trophoblast stem cell (TSC) differentiation. The transcriptome of different cell types were analyzed and compared to identify a TSC gene signature. In order to identify novel TSC specific genes, we performed genome-wide expression profiling of TSCs, embryonic stem cells, epiblast stem cells, and mouse embryo fibroblasts derived from mice of the same genetic background (129S1/SvImJ).

2015-11-10 | E-GEOD-67037 | biostudies-arrayexpress

ChIP-seq on Olig2, Ascl1, Tcf3, Max, NFI, Sox2, Sox9 and Sox21 in mouse neural stem cells

Project description:Definition of genome wide binding profile of Olig2, Ascl1, Tcf3, Max, NFI, Sox2, Sox9 and Sox21 in mouse neural stem cells. Three sets of processed data files, together with a README file (README_E-MTAB-2228.docx) describing the source and content of each file, are provided as additional files to this ArrayExpress submission and can be found in https://www.ebi.ac.uk/arrayexpress/files/E-MTAB-2228 .

2014-09-19 | E-MTAB-2228 | biostudies-arrayexpress

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