SOX21 Ensures Rostral Forebrain Identity by Suppression of WNT8B during Neural Regionalization of Human Embryonic Stem Cells

Fang, Zhuoqing; Liu, Xinyuan; Wen, Jing; Tang, Fan; Zhou, Yang; Jing, Naihe; Jin, Ying

doi:10.1016/j.stemcr.2019.10.013

Cited by 16 publications

(12 citation statements)

References 41 publications

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“…SOX3 down-regulates Wnt signaling by interactions with β-catenin or by direct binding to the regulatory regions of Wnt target genes ( Zorn et al, 1999 ; Zhang et al, 2003 ). SOX21 restricts Wnt activity by interacting with β-catenin and subsequent interfering with the binding of TCF4/β-catenin complex to the WNT8B (Wingless-type MMTV integration site family, member 8B) enhancer ( Fang et al, 2019 ).…”

Section: Sox Interplay With Wnt/β-catenin Signalingmentioning

confidence: 99%

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Stevanović

Drakulić

Lazic

et al. 2021

Front. Mol. Neurosci.

104

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The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodegenerative diseases, could be associated with deregulation of SOX proteins activities. We present the current data regarding the interaction between SOX proteins and signaling pathways and microRNAs that play roles in nervous system development. Finally, future research directions that will improve the knowledge about distinct and various roles of SOX TFs in health and diseases are presented and discussed.

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Section: Sox Interplay With Wnt/β-catenin Signalingmentioning

confidence: 99%

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Stevanović

Drakulić

Lazic

et al. 2021

Front. Mol. Neurosci.

104

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“…RNA samples of undifferentiated hESCs (day 0) and NPCs from these three groups at days 4 and 8 were collected for RNA-seq ( Figure 3 C). Compared with our previously published RNA-seq data of WT samples ( Fang et al., 2019 ), DEGs were identified ( Figure 3 D). Among the three groups of NPCs, SOX1 -KO gave rise to the most DEGs in the CT1.0 group and the least DEGs in the IWP2 group ( Figure 3 D), suggesting that SOX1 -KO affected NPCs of the CT1.0 group most.…”

Section: Resultsmentioning

confidence: 73%

“…Moreover, both up- and downregulated DEGs enriched the term of WNT signaling. In addition, based on our previously published dataset ( Fang et al., 2019 ), clustering analysis of DEGs revealed that the SOX1 -KO NPCs (CT1.0) were grouped with WT NPCs of CT0.8 and CT0.4 groups ( Figure 3 F), suggesting that the regional identity of SOX1 - KO NPCs of the CT1.0 group was closer to that of WT NPCs of CT0.8 and CT0.4 groups than to that of WT NPCs of the CT1.0 group. In contrast, the SOX1 -KO NPCs treated with IWP2 or 0.4 μM CT were grouped with WT NPCs under the same treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of differentially expressed genes (DEGs) identified 170 genes enriched in EGFP high cells and 336 genes enriched in EGFP low cells (fold changes >1.5 and false discovery rate [FDR] < 0.05). Based on our previously published dataset obtained from positionally patterned NPCs derived from WT hESCs (Fang et al, 2019), clustering analysis of DEGs revealed that the EGFP high cells were grouped with NPCs treated with 0.8-2.0 mM CT, whereas EGFP low cells were grouped with NPCs treated with 0.4 mM CT ( Figure S3A). Moreover, as indicated by the volcano plot, OTX1, OTX2, LMX1A, LMX1B, EN1, WNT1, and WNT3A were enriched in the EGFP low cells, whereas GBX2, HOXA1, HOXA2, and SOX1 were enriched in the EGFP high cells ( Figure 2C).…”

Section: Otx2 Inhibits Sox1 Expressionmentioning

confidence: 95%

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SOX1 Is Required for the Specification of Rostral Hindbrain Neural Progenitor Cells from Human Embryonic Stem Cells

et al. 2020

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Region-specific neural progenitor cells (NPCs) can be generated from human embryonic stem cells (hESCs) by modulating signaling pathways. However, how intrinsic transcriptional factors contribute to the neural regionalization is not well characterized. Here, we generate region-specific NPCs from hESCs and find that SOX1 is highly expressed in NPCs with the rostral hindbrain identity. Moreover, we find that OTX2 inhibits SOX1 expression, displaying exclusive expression between the two factors. Furthermore, SOX1 knockout (KO) leads to the upregulation of midbrain genes and downregulation of rostral hindbrain genes, indicating that SOX1 is required for specification of rostral hindbrain NPCs. Our SOX1 chromatin immunoprecipitation sequencing analysis reveals that SOX1 binds to the distal region of GBX2 to activate its expression. Overexpression of GBX2 largely abrogates SOX1-KO-induced aberrant gene expression. Taken together, this study uncovers previously unappreciated role of SOX1 in early neural regionalization and provides new information for the precise control of the OTX2/GBX2 interface.

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“…Previously, we have shown that SOX21 is required for reprogramming to the pluripotent state and regulates the anterior-posterior identity in the adult mouse intestine (Kuzmichev et al, 2012). Other laboratories have reported SOX21 roles in embryonic versus extraembryonic fate at the 4-cell stage (Goolam et al, 2016), later events in forebrain development (Fang et al, 2019), and adult hippocampal neurogenesis (Matsuda et al, 2012). These data suggest that SOX21 repeatedly interacts with other class B SOX genes (SOX1, 2, and 3) to regulate major morphogenetic decisions.…”

Section: Resultsmentioning

confidence: 99%

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

Kim¹,

Seo

Stein-O’Brien³

et al. 2021

Preprint

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SUMMARYVariability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. We identify differences in the spontaneous self-organization of individual hPSC lines during self-renewal that lie along a fundamental axis of in vivo development. Distinct stable and dynamic transcriptional elements were revealed by decomposition of RNA-seq data in pluripotency and early lineage emergence. Stable differences within pluripotency predicted regional bias in the dynamics of neural differentiation that were also observed in large collections of hPSC lines. Using replicate human induced PSC (hiPSC) lines and paired adult tissue, we demonstrate that cells from individual humans expressed unique transcriptional signatures that were maintained throughout life. In addition, replicate hiPSC lines from one donor showed divergent expression phenotypes driven by distinct chromatin states. These stable transcriptional states are under both genetic and epigenetic control and predict bias in subsequent forebrain and hindbrain neural trajectories. These results define mechanisms controlling transcription in pluripotency to first establish human neural diversity. Data availability: GSE164055; https://nemoanalytics.org/p?l=KimEtAL2021&g=GBX2.Abstract Figure

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SOX21 Ensures Rostral Forebrain Identity by Suppression of WNT8B during Neural Regionalization of Human Embryonic Stem Cells

Cited by 16 publications

References 41 publications

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

SOX1 Is Required for the Specification of Rostral Hindbrain Neural Progenitor Cells from Human Embryonic Stem Cells

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

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