Snf2l Regulates Foxg1-Dependent Progenitor Cell Expansion in the Developing Brain

Abstract

SUMMARY Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size.

ATP-dependent chromatin remodeling during mammalian development

“…Snf2h (Smarca5) is expressed ubiquitously across a variety of tissue types, and is required for early embryonic development, whereas Snf2l (Smarca1) appears to be restricted to post-natal reproductive tissues and the brain (Lazzaro and Picketts, 2001;Stopka and Skoultchi, 2003). Consistent with these observations, Snf2h but not Snf2l is essential for survival, and Snf2l-knockout mice survive and reproduce normally (Yip et al, 2012). Below, we describe the developmental roles of different ISWI complexes.…”

“…Conditional deletion of Snf2l increases neural progenitor proliferation and self-renewal, and expression of the transcription factor FOXG1. SNF2L directly represses Foxg1 expression by occupying its promoter region, hence maintaining a balance between neural progenitor proliferation and subsequent differentiation during brain development (Yip et al, 2012). Another SNF2L-containing complex comprising SNF2L and CECR2, called the CERF complex, is involved in neurulation.…”

“…Both SNF2H-and SNF2L-containing complexes are also essential during the development of ectoderm-derived lineages (Alvarez-Saavedra et al, 2014;Barak et al, 2003;Koludrovic et al, 2015;Yip et al, 2012). During nervous system development (Fig.…”

“…NURF is required during post-implantation embryonic development and ESC differentiation (Landry et al, 2008) and for thymocyte maturation (Landry et al, 2011) CERF SNF2L, CECR2 SNF2L is required during neurogenesis (Yip et al, 2012) and oogenesis (Pépin et al, 2013) CERF is involved in neurulation (Banting et al, 2005) *Current mouse gene symbols are listed only where they differ from protein nomenclature.…”

The Imitation Switch ATPase Snf2l Is Required for Superovulation and Regulates Fgl2 in Differentiating Mouse Granulosa Cells

“…In the brain, SNF2L regulates the expression of engrailed 1 and 2 and promotes neurite outgrowth as part of the nucleosome remodeling factor (NURF) complex [4]. Mice bearing a deletion of the Snf2l exon 6 (Ex6DEL), disrupting the ATPase domain, display increased progenitor cell expansion and delayed differentiation of neurons in the forebrain along with a dysregulation of Foxg1 [5].…”