The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression
Danielle E. Whittaker ... Cathy Fernandes, M. Albert Basson
Danielle E. Whittaker ... Cathy Fernandes, M. Albert Basson
Published March 1, 2017
Citation Information: J Clin Invest. 2017;127(3):874-887. doi:10.1172/JCI83408.
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Categories: Research Article Development Neuroscience

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.

Authors

Danielle E. Whittaker, Kimberley L.H. Riegman, Sahrunizam Kasah, Conor Mohan, Tian Yu, Blanca Pijuan Sala, Husam Hebaishi, Angela Caruso, Ana Claudia Marques, Caterina Michetti, María Eugenia Sanz Smachetti, Apar Shah, Mara Sabbioni, Omer Kulhanci, Wee-Wei Tee, Danny Reinberg, Maria Luisa Scattoni, Holger Volk, Imelda McGonnell, Fiona C. Wardle, Cathy Fernandes, M. Albert Basson

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Deletion of Chd7 from GCps results in PC abnormalities. (A) PC counts in...

Figure 3

Deletion of Chd7 from GCps results in PC abnormalities.

(A) PC counts in cn and cko mouse P21 cerebella. Note the significant reduction in total PC number in the cko. (B) Lobule-specific PC counts. Note the significant reduction in PC number in the anterior and central lobules of the cko. (C–E) PC density in relation to the total vermis volume (mm3) (C), lobule granule cell area (mm2) (D), and length of the PC layer (mm) (E) (n ≥ 5 per genotype). *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test. (F–U) Examples of Purkinje cell protein 2 (PCP2) immunostains to visualize PCs in P7 cerebellar sections through the vermis (F–I) or hemispheres (J–M), with nuclear DAPI counterstain, anterior to the left. Magnified views of PC layers indicated by white boxed areas in corresponding low-power images are depicted in H, I, L, and M. Note the occasional disorganized PC distribution in the cko vermis (I), and more pronounced clusters of mislocalized PCs in the cko cerebellar hemispheres (M). (N–U) Examples of PCP2 immunostains to visualize PCs in P21 cerebellar sections through the vermis (N–Q) or hemispheres (R–U), with nuclear DAPI counterstain, anterior to the left. Magnified views of PC layers indicated by white boxed areas in corresponding low-power images are depicted in P, Q, T, and U. Note the occasional multilayered PC distribution in the cko vermis (Q), and more pronounced clusters of mislocalized PCs in the cko cerebellar hemispheres (U). Scale bars: 300 μm (F), 100 μm (H and P), 1 mm (N).