Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome

Abstract

Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. The clinical features of CHARGE syndrome are highly variable and incompletely penetrant. Olfactory dysfunction is a common feature in CHARGE syndrome and has been potentially linked to primary olfactory bulb defects, but no data confirming this mechanistic link have been reported. On the basis of these observations, we hypothesized that loss of Chd7 disrupts mammalian olfactory tissue development and function. We found severe defects in olfaction in individuals with CHD7 mutations and CHARGE, and loss of odor evoked electro-olfactogram responses in Chd7 deficient mice, suggesting reduced olfaction is due to a dysfunctional olfactory epithelium. Chd7 expression was high in basal olfactory epithelial neural stem cells and down-regulated in mature olfactory sensory neurons. We observed smaller olfactory bulbs, reduced olfactory sensory neurons, and disorganized epithelial ultrastructure in Chd7 mutant mice, despite apparently normal functional cilia and sustentacular cells. Significant reductions in the proliferation of neural stem cells and regeneration of olfactory sensory neurons in the mature Chd7(Gt/+) olfactory epithelium indicate critical roles for Chd7 in regulating neurogenesis. These studies provide evidence that mammalian olfactory dysfunction due to Chd7 haploinsufficiency is linked to primary defects in olfactory neural stem cell proliferation and may influence olfactory bulb development.

The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear

“…Gt/+ mutant mice also have defects in innervation to the adult posterior crista within the ear , and reduced neural stem cell proliferation in the olfactory epithelium (Layman et al, 2009). CHD7 belongs to a family of nine mammalian CHD proteins characterized by the presence of two chromodomains N-terminal to an SNF2 ATP-dependent helicase domain (Woodage et al, 1997).…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…Chd7 is highly expressed in olfactory epithelial neural stem and progenitor cells, as demonstrated by colocalization with Ascl1 and Neurod1 [61]. In mice, loss of Chd7 correlates with a marked decrease in olfactory epithelial neural stem cell proliferation, a subsequent reduction in olfactory sensory neurons, and impaired recovery from damage [61]. Interestingly, Chd7 heterozygous mutant mice also show decreased dopaminergic tyrosine hydroxylase-positive interneurons in the olfactory bulb, which could be due to impaired efferent signals from the olfactory epithelium or a defect in olfactory bulb neurogenesis from the SVZ neural stem cell niche [61].…”

“…Olfactory deficits are commonly accompanied by hypoplasia or aplasia of the olfactory bulbs in the brain [55,[60][61][62]. It was discovered, through electrophysiological and behavioral assays, that Chd7 heterozygous mice display complete anosmia, lack of odor discrimination, and olfactory bulb hypoplasia [61,63].…”

“…It was discovered, through electrophysiological and behavioral assays, that Chd7 heterozygous mice display complete anosmia, lack of odor discrimination, and olfactory bulb hypoplasia [61,63]. Chd7 is highly expressed in olfactory epithelial neural stem and progenitor cells, as demonstrated by colocalization with Ascl1 and Neurod1 [61]. In mice, loss of Chd7 correlates with a marked decrease in olfactory epithelial neural stem cell proliferation, a subsequent reduction in olfactory sensory neurons, and impaired recovery from damage [61].…”

“…In mice, loss of Chd7 correlates with a marked decrease in olfactory epithelial neural stem cell proliferation, a subsequent reduction in olfactory sensory neurons, and impaired recovery from damage [61]. Interestingly, Chd7 heterozygous mutant mice also show decreased dopaminergic tyrosine hydroxylase-positive interneurons in the olfactory bulb, which could be due to impaired efferent signals from the olfactory epithelium or a defect in olfactory bulb neurogenesis from the SVZ neural stem cell niche [61]. Thus, olfactory processing depends on CHD7 function not only in the peripheral olfactory epithelium but also in central nervous system-derived neurogenic niches.…”