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

J Clin Invest. 2017 Mar 1;127(3):874-887. doi: 10.1172/JCI83408. Epub 2017 Feb 6.

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.

MeSH terms

  • Animals
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cerebellum / abnormalities
  • Cerebellum / embryology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Developmental Disabilities / genetics
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Gene Expression Regulation, Developmental*
  • Genetic Loci*
  • Genome-Wide Association Study
  • Humans
  • Mice
  • Mice, Transgenic
  • Motor Disorders / genetics
  • Motor Disorders / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nervous System Malformations / embryology
  • Nervous System Malformations / genetics
  • Neural Stem Cells / metabolism*
  • Neurogenesis*
  • Reelin Protein
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Chd7 protein, mouse
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Reelin Protein
  • RELN protein, human
  • Reln protein, mouse
  • Serine Endopeptidases

Supplementary concepts

  • Cerebellar Hypoplasia