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 February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):874-887. https://doi.org/10.1172/JCI83408.
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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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Figure 4

Deletion of Chd7 from GCps leads to developmental delay and motor coordination deficits.

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Deletion of Chd7 from GCps leads to developmental delay and motor coordi...
Behavioral assessments of separate cohorts of adult (D–F, H, and I) cn (male n = 12, female n = 11) and cko (male n = 10, female n = 12) mice and pups for analysis of developmental milestones (cn n = 20, cko n = 22) or ultrasonic vocalizations (USVs) (cn n = 21, cko n = 23). (A–C) The percentage of pups at the indicated postnatal ages demonstrating the full righting reflex (A), a score of 1 or higher for negative geotaxis (B), or the full reaching response (C). Note the delay in acquiring these motor milestones in cko compared with cn animals (*P ≤ 0.05, χ2 tests). (D and E) The mean latency of male (D) and female (E) mice to fall from the rotarod. Note the significant difference between the male cko and cn animals (*P ≤ 0.05, repeated-measures ANOVA, with Student’s t test as post hoc analysis). (F) The mean number of ultrasonic vocalizations per minute at the indicated postnatal ages for cn and cko mice (repeated-measures ANOVA). (G) Average number of marbles buried within 30 minutes. Note no significant difference between the groups (between-subjects ANOVA). (H and I) The mean duration of total social investigation of an age- and sex-matched novel conspecific at P21 (H) and in adulthood (I). No significant difference between the cn and the cko groups was observed (repeated-measures ANOVA).