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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; First published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):874-887. https://doi.org/10.1172/JCI83408.
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Categories: Research Article Development Neuroscience

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

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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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Figure 1

Chd7 deletion from embryonic neural progenitors causes cerebellar hypoplasia and foliation abnormalities.

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Chd7 deletion from embryonic neural progenitors causes cerebellar hypop...
(A–D) In situ hybridization for Chd7 exon 3 transcripts (blue) in sagittal sections through P0 Chd7fl/fl (control [cn]) and nestin-Cre Chd7fl/fl (cko) brains. Sections through the cerebellar vermis (A and B) and hemispheres (C and D) are shown. Note Chd7 expression in the olfactory bulb (OB), neocortex (NC), thalamus (Th), hypothalamus (Hy), hippocampus (HC), ventricular zone (VZ), rostral migratory stream (RMS), and cerebellum (Cb) in cn sections (A and C), absent in the cko (B and D). (E and F) Whole-mount images (anterior to the top) with cerebellum outlined. (G and H) High-power images with cerebella outlined. SC, superior colliculus; IC, inferior colliculus. (I–N) Cresyl violet–stained sagittal sections through the cerebellum, anterior to the left, with vermis folia labeled with Roman numerals according to Inouye and Oda (77). The simplex (S), Crus I (CI), Crus II (CII), paramedian (PM), and pyramidis (P) folia are labeled in hemisphere sections. Note cerebellar hypoplasia (J and L) and disorganized folia in cko hemispheres (L, boxed area). Note the expansion of lobules IV–V and IX from vermis into the hemispheres (L, red text). (M and N) Magnified view of the boxed areas in K and L with PC layers outlined in broken red lines. Ectopic granule cells organized around a circular cluster of PCs are indicated with a black arrowhead. WM, white matter. (O–X) Cresyl violet–stained sections through the developing cerebellum at the time points indicated, anterior to the left, with cerebellar folia labeled as above. Note the vermis hypoplasia at E16.5 and P0, and striking hypoplasia of both vermis and hemispheres at P14 (V and X) in the cko. Mb, midbrain. Scale bars: 1 mm (A, E, I, and O), 300 μm (G and U), 100 μm (M).
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ISSN: 0021-9738 (print), 1558-8238 (online)

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