Human ESC-Derived Neural Crest Model Reveals a Key Role for SOX2 in Sensory Neurogenesis

Cimadamore, Flavio; Fishwick, Katherine; Giusto, Elena; Gnedeva, Ksenia; Cattarossi, Giulio; Miller, Amber; Pluchino, ﻿Stefano; Brill, Laurence M.; Bronner‐Fraser, Marianne; Terskikh, Alexey V.

doi:10.1016/j.stem.2011.03.011

Cited by 90 publications

(127 citation statements)

References 60 publications

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“…Our previous microarray gene expression analysis of hESC-derived multipotent NPCs (11,30,31) suggested that SOX2 regulates the expression of LIN28, a well-studied repressor of let-7 family biosynthesis (13)(14)(15)(16). Immunofluorescence analysis confirmed that SOX2 and LIN28 were coexpressed in all NPCs (Fig.…”

Section: Sox2mentioning

confidence: 64%

“…We previously found that knocking down SOX2 precludes NPC differentiation into neurons without affecting glial fates (11). Indeed, SOX2 knockdown in NPCs cultured under conditions favoring neuronal differentiation strongly reduced the appearance of young TUJ1+ neurons ( Fig.…”

Section: Lin28 Modulates Npc Proliferation and Neuronal Commitmentmentioning

confidence: 73%

“…1A). We used NPCs derived from a hESC line carrying a doxycycline (dox)-inducible SOX2 shRNA (11) to knock down SOX2 and monitor the expression of LIN28 transcripts. Following dox treatment, we observed loss of SOX2 expression with concomitant and proportional loss of LIN28, as measured by quantitative PCR…”

Section: Sox2mentioning

confidence: 99%

“…SOX2 is also required for neurogenesis in the central nervous system (7)(8)(9)(10). Recently, we used human embryonic stem cells (hESCs) and mouse models to demonstrate a critical requirement for SOX2 for sensory neurogenesis in dorsal root ganglia (11). However, the mechanisms by which SOX2 functions in self-renewal and neuronal differentiation remain poorly understood.…”

mentioning

confidence: 99%

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SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Cimadamore

Amador-Arjona

Chen

et al. 2013

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

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The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cellderived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2-LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential.neural stem cells | mechanisms of pluripotency S elf-renewing, multipotent neural precursor cells (NPCs) are capable of terminally differentiating into neuronal and glial lineages during development and in the adult nervous system (1, 2). Disruption of the pathways controlling NPC biology has been implicated in various pathologies, including autism (3), Treacher Collins syndrome (4), and neural tube defects (5), emphasizing the importance of gaining a better understanding of the underlying molecular events and how they may be manipulated to treat and prevent such pathologies. The HMG-box transcription factor SOX2 is ubiquitously expressed in NPCs and supports their self-renewal (6). SOX2 is also required for neurogenesis in the central nervous system (7-10). Recently, we used human embryonic stem cells (hESCs) and mouse models to demonstrate a critical requirement for SOX2 for sensory neurogenesis in dorsal root ganglia (11). However, the mechanisms by which SOX2 functions in self-renewal and neuronal differentiation remain poorly understood.Small, noncoding microRNAs (miRNAs) are transcribed as long precursors (pri-miRNAs) that are sequentially processed by the RNases Drosha/Pasha to form pri-miRNAs and by Dicer to form the mature miRNAs of ∼20-25 nucleotides. The miRNAs function through imperfect base-pairing with hundreds of target mRNAs to trigger their degradation (or block their translation) by the RNA-induced silencing complex, RISC (12). In some cases, miRNA maturation is tightly controlled; for example, the RNA-binding protein LIN28 regulates the biogenesis of the let-7 miRNA family by inhibiting their maturation at both the primiRNA (13, 14) and premiRNA (15, 16) processing steps. Intriguingly, LIN28 protein was found to be associated with SO...

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Section: Sox2mentioning

confidence: 64%

Section: Lin28 Modulates Npc Proliferation and Neuronal Commitmentmentioning

confidence: 73%

Section: Sox2mentioning

confidence: 99%

mentioning

confidence: 99%

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SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Cimadamore

Amador-Arjona

Chen

et al. 2013

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

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200

182

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“…Rather, it is involved in a variety of fetal and adult stem cells, such as neural stem cells, retina and pituitary progenitor cells. [38][39][40][41] At the molecular level, Sox2 serves as a pioneer factor and is involved in cell fate determination through its dynamic interactions with different protein partners for transcriptional regulation of corresponding sets of target genes. [42][43][44][45] For example, in undifferentiated ES cells, Sox2 forms a heterodimer with Oct4 to activate stemness-related genes while repressing differentiationspecific genes.…”

Section: Discussionmentioning

confidence: 99%

Ube2s regulates Sox2 stability and mouse ES cell maintenance

et al. 2015

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Sox2 has a critical role in embryonic stem (ES) cell maintenance and differentiation. Interestingly, its activity is highly dosagedependent. Although transcriptional regulation of Sox2 has been extensively studied, the mechanisms orchestrating its degradation remain unclear. In this study, we identified ubiquitin-conjugating enzyme E2S (Ube2s) as a novel effector for Sox2 protein degradation. Ube2s mediates K11-linked polyubiquitin chain formation at the Sox2-K123 residue, thus marking it for proteasome-mediated degradation. Besides its role in fine-tuning the precise level of Sox2, Ube2s reinforces the self-renewing and pluripotent state of ES cells. Importantly, it also represses Sox2-mediated ES cell differentiation toward the neural ectodermal lineage.

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Isolation and differentiation properties of neural crest stem cells

Dupin

Coelho-Aguiar

2012

Cytometry Pt A

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A wide array of neural and non-neural cell types arises from the neural crest during vertebrate embryogenesis. The neural crest forms transiently in the dorsal neural primordium to yield migratory cells that will invade nearly all tissues and later, differentiate into bones and cartilages, vascular smooth muscle cells, connective tissues, neurons and glial cells of the peripheral nervous system, endocrine cells, and melanocytes. Due to the amazingly diversified array of cell types they generate, the neural crest cells represent an attractive model in the stem cell field. We review here in vivo and in vitro studies of individual cells, which led to the discovery and characterization of neural crest progenitors endowed with multipotency and stem cell properties. We also present an overview of the diverse types, marker expression, and locations of the neural crest-derived stem cells identified in the vertebrate body, with emphasis on those evidenced recently in mammalian adult tissues. ' 2012 International Society for Advancement of Cytometry

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Human ESC-Derived Neural Crest Model Reveals a Key Role for SOX2 in Sensory Neurogenesis

Cited by 90 publications

References 60 publications

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Ube2s regulates Sox2 stability and mouse ES cell maintenance

Isolation and differentiation properties of neural crest stem cells

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