The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression

Abstract

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…The analysis of GCp‐specific Chd7 conditional mutant mice has identified important roles for CHD7 in regulating GCp apoptosis, proliferation and differentiation in the perinatal cerebellum (Feng et al, 2017; Whittaker et al, 2017). However, a reduction in GCp expansion is by itself not sufficient to explain the cerebellar foliation defects described here.…”

“…In fact, in later stages of cerebellar development, En1/2 are essential for anterior‐posterior and medial‐lateral patterning of the cerebellum (Cheng et al, 2010; Joyner et al, 1991; Sgaier et al, 2007; Sillitoe et al, 2008; Sillitoe et al, 2010). Interestingly, our recent RNA‐seq analysis of Chd7 ‐deficient cerebellar GCps showed that En1 expression was upregulated in these cells, implicating CHD7 as a potential repressor of En1 expression (Whittaker et al, 2017). It is tempting to speculate that dysregulated En1 expression contributes to the specific foliation anomalies we have identified in Chd7 ‐deficient mice.…”

“…Separately, the relationship between cerebellar anomalies and autism is well established and in contrast to other brain regions, gross and microscopic changes in the cerebellum are most frequently associated with autism (Becker & Stoodley, 2013). However, we previously reported that cerebellar hypoplasia and foliation defects in Chd7 GCp‐specific conditional mouse mutants, alone were not sufficient to lead to social deficits (Whittaker et al, 2017). The contribution of cerebellar dysfunction to autistic phenotypes in patients also remains unclear.…”

“…The introduction of CHARGE syndrome‐associated mutations in the ATP‐dependent chromatin remodeling and chromodomains of CHD7, tested in nucleosome remodeling assays, provided proof that chromatin remodeling activity is central to the pathogenesis of CHARGE syndrome (Bouazoune & Kingston, 2012). We recently reported changes in DNA accessibility at thousands of putative gene regulatory elements in Chd7 ‐deficient cerebellar neuron progenitors, providing in vivo evidence that altered nucleosome remodeling underlies specific phenotypes associated with CHD7 deficiency (Whittaker et al, 2017). …”

“…Diminished FGF signaling contributes specifically to hypoplasia of the cerebellar vermis (Yu et al, 2013). During the peri‐ and early postnatal stages of development, Chd7 is highly expressed in granule cell progenitors (GCps) on the surface of the cerebellar anlage, where it regulates cerebellar growth by controlling the proliferation, differentiation, and survival of this cell population (Whittaker et al, 2017). …”