MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis

Abstract

SummaryThe generation of neurons from neural stem cells requires large-scale changes in gene expression that are controlled to a large extent by proneural transcription factors, such as Ascl1. While recent studies have characterized the differentiation genes activated by proneural factors, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 while promoting neuronal differentiation. We combined functional studies of MyT1 during neurogenesis with the characterization of its transcriptional program. MyT1 binding is associated with repression of gene transcription in neural progenitor cells. It promotes neuronal differentiation by counteracting the inhibitory activity of Notch signaling at multiple levels, targeting the Notch1 receptor and many of its downstream targets. These include regulators of the neural progenitor program, such as Hes1, Sox2, Id3, and Olig1. Thus, Ascl1 suppresses Notch signaling cell-autonomously via MyT1, coupling neuronal differentiation with repression of the progenitor fate.

mSEL‐1L deficiency affects vasculogenesis and neural stem cell lineage commitment

“…This is often referred to the decrement of Notch ligand from neighboring cells (Nelson, Hodge, Bedogni, & Hevner, 2013), that results in repression of target genes through the action on corepressors recruited by RBPJ. However, recent studies suggest the possibility of cell-autonomous mechanisms to inhibit the Notch-1 program (Kawaguchi et al, 2008;Nelson et al, 2013;Vasconcelos et al, 2016). One contribution to these mechanisms can be the lowering of mSEL-1L outside the germinal niches.…”

Notch/Hes signaling and miR-9 engage in complex feedback interactions controlling neural progenitor cell proliferation and differentiation

“…Once the cells have embarked for differentiation they do not only down-regulate Notch activity but also the responsiveness of the Hes1 promoter toward NICD/RPBj transcriptional complex 24-26 . In this context, the transcriptional repressor MyT1 has recently been found to negatively regulate Hes1 expression and to counteract Notch-mediated activation of the Hes1 locus 27 . The expression of MyT1 itself is negatively coupled to Notch activity via its transcriptional activator Ascl1 27 .…”

Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function

“…Overall, we inferred that the substantial up-regulation in late-acting stress-response gene expression in 6F; Pdx1 Cre islets was not mediated by the early-acting UPR sensor-effectors, and consequently postulated that the Myt TFs normally work to directly repress transcription of these late-stage stress-pathway genes. Supporting this hypothesis, in silico analysis and data mining of published ChIP-seq data derived from fibroblasts and neuronal progenitors (Bellefroid et al, 1996;Mall et al, 2017;Vasconcelos et al, 2016) have identified several putative Myt TF binding sites (proposed AAGTT consensus, Bellefroid et al, 1996) within 5' cis-regulatory regions of Atf4, Hspa1a, Hspa1b, HspH1, and Dnajb1 ( Figure 3B), although their significance to expression of these stress-pathway genes was not reported.…”

“…Myt1 significantly activated expression of the Hspa1a, Hspa1b, HspH1, and Atf4 reporters, but not Dnajb1. The more modest effect on Dnajb1-driven transcription could reflect the absence in our construct of an additional Myt-binding site detected at roughly -6 kbp in fibroblasts and neuronal cells (Mall et al, 2017) (Vasconcelos et al, 2016), because 5'-flanking control regions containing this putative binding site were for unknown reasons unclonable. Note that while we were probing the mechanisms for the transcriptionally repressive effects of Myt TFs on stress-pathway genes that we had detected in pancreatic  cells, these out-of-context assays in HEK293T cells showed activation not repression, which we expected based on the similar "reversals" that occurred when testing the AAGTT motifs in artificial in vitro reporter-transfection assays (Bellefroid et al, 1996;Manukyan et al, 2018;Yee and Yu, 1998).…”

“…For example, hyperglycemia and hyperlipidemia potentiate Myt3 expression in β cells (Henry et al, 2014;Tennant et al, 2012), a response associated either with cell survival (Henry et al, 2014) or cell death (Tennant et al, 2016). This family of zinc-finger proteins is also expressed in neural and neuro-endocrine cells (Gu et al, 2004;Henry et al, 2014;Kim and Hudson, 1992;Tennant et al, 2012;Vasconcelos et al, 2016;Wang et al, 2007), wherein they regulate cell differentiation by repressing expression of non-neuronal genes (Vasconcelos et al, 2016). Precisely defining Myt1, 2 and/or 3 activities, however, has been greatly hampered by the genetic compensation between the members (Wang et al, 2007).…”