Delayed fusion and altered gene expression contribute to semicircular canal defects in Chd7 deficient mice

Abstract

Summary Proper morphogenesis of inner ear semicircular canals requires precise regulation of cellular proliferation, epithelial-to-mesenchymal transition, and fusion of epithelial plates. Epigenetic regulation of these processes is not well understood, but is likely to involve chromatin remodeling enzymes. CHD7 is a chromodomain-containing, ATP dependent helicase protein that is highly expressed in the developing ear and is required for semicircular canal development in both humans and mice. Here we report that mice with heterozygous loss of Chd7 function exhibit delayed semicircular canal genesis, delayed Netrin1 expression and disrupted expression of genes that are critical for semicircular canal formation (Bmp2, Bmp4, Msx1 and Fgf10). Complete loss of Chd7 results in aplasia of the semicircular canals and sensory vestibular organs, with reduced or absent expression of Otx1, Hmx3, Jagged1, Lmo4, Msx1 and Sox2. Our results suggest that Chd7 may have critical selector gene functions during inner ear morphogenesis. Detailed analysis of the epigenetic modifications underlying these gene expression changes should provide insights into semicircular canal development and help in the design of therapies for individuals with inner ear malformations.

CT findings of the temporal bone in CHARGE syndrome: aspects of importance in cochlear implant surgery

“…CHD7 is highly expressed in the developing ear and is required for development of the SCCs. Delayed fusion and altered gene expression contribute to SCC defects in CHD7 -deficient mice [16]. Currently, the presence of SCC abnormalities is considered an important indication for performing sequencing of the CHD7 gene and diagnosis [17].…”

CHD7 Mutations and CHARGE Syndrome in Semicircular Canal Dysplasia

“…Mice with CHD7 deficiency exhibit defects in vestibular sensory epithelial innervation 35 . CHD7 regulates inner ear neurogenesis, and Chd7 conditional knockout and null mice have reduced vestibulo-cochlear ganglion size, neuron number, and expression of patterning and pro-neural genes 4 . Mutations in CHD7 can result in a much milder phenotype than that of classical CHARGE syndrome 29 .…”

“…It is a relatively common, but often underappreciated cause of deafness, with a prevalence of 1:8,500 to 1:15,000 1–3 . CHARGE was originally defined by the presence of ocular C oloboma, H eart disease, A tresia choanae, R etarded growth, G enital hypoplasia, and E ar anomalies 4,5 . Affected individuals often have additional clinical features, including cranial nerve dysfunction, esophageal anomalies, facial clefts, feeding difficulties, arrhinencephaly, agenesis of the semicircular canals, hypothalamo-hypophyseal dysfunction, and characteristic square facies with a broad forehead and prominent nasal bridge 6–10 .…”

“…CHD7 is involved in the expression of patterning and pro-neural genes within the otic epithelium and ganglion, and deficiency results in decreased neurogenesis in the inner ear 27 . Mice with heterozygous loss of Chd7 have delayed semicircular canal genesis and disrupted expression of genes required for semicircular canal formation, whereas mice with complete loss of Chd7 have semicircular canal aplasia and vestibular organ agenesis 4 . In light of these recent findings, CHD7 most likely has critical selector gene functions during inner ear morphogenesis 4 .…”

Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration

“…These defects are in part due to an abnormal pattern of cell proliferation. In addition, analysis of heterozygous Chd7 mutant and conditional Chd7 knockout mice revealed that CHD7 regulates the expression of vestibular regulatory genes in a gene dosage dependent manner [76]. Interestingly, inhibition of retinoic acid (RA) signaling can rescue semicircular canal defects in heterozygous Chd7 mutant mice, suggesting that hyperactive RA signaling contributes to inner ear malformations in Chd7 mutants [77].…”