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

Abstract

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...

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

“…In our previous study focusing on the LIN28 gene, which is fully active in NPCs, we found that SOX2 promotes an open chromatin state at the promoter (H3K9ac mark) through recruitment of the TRRAP/GCN5 complex (56). Here, we uncovered a distinct epigenetic mechanism of SOX2 function on poised proneural and early neurogenic genes in NPCs.…”

“…The cell-cycle deficits observed in these proliferating cells likely result from the reduced expression of Lin28. Our previous work showed that SOX2 directly controls Lin28 expression in several types of NPCs, and Lin28 rescues the proliferation defect in SOX2-deficient NPCs through effects on cell-cycle regulators such as CyclinD1, TLX, and CDC25A (56). On the other hand, the absence of a cell-cycle deficit in SOX2-deficient radial glia stem cells is consistent with the limited self-renewal of this stem cell population (48).…”

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

“…Recently, Wang et al [5] reported that SOX2 knockdown (KD) caused a compensational increase in SOX3 expression and that simultaneous depletion of SOX2 and SOX3 led to primitive streak induction in hESCs. Also, SOX2 KD was reported to affect hNPCs proliferation and neurogenesis rather than apoptosis through a SOX2-Lin28/let7 pathway [6]. Apart from these studies, how SOX2 exerts cell type-dependent roles in these two distinct and developmentally related cell types is largely unknown.…”

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

“…2). Because Sox2 has recently been shown to bind to the promoters of poised pro-neural genes in NPCs to enable an appropriate neuronal differentiation (32,35) program, including the neurogenic genes Ngn2 and NeuroD1, we reasoned that RIT1-dependent neurogenic gene expression might rely on Sox2 activation. Indeed, active RIT1 expression both increases Sox2 protein levels (Fig.…”