Human Molecular Genetics Advance Access originally published online on March 11, 2009
Human Molecular Genetics 2009 18(11):1909-1923; doi:10.1093/hmg/ddp112
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Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome
1 Department of Human Genetics 2 Department of Pharmacology 3 Department of Otolarynology 4 Department of Pediatrics, University of Michigan Medical Center, 3520A Medical Science Research Building I, Ann Arbor, MI 48109-5652, USA 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 6 Neurobiology Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute / NIH, Bethesda, MD 20892, USA 7 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
* To whom correspondence should be addressed. Tel: +1 7346474859; Fax: +1 7347639512; Email: donnamm{at}umich.edu
Received December 5, 2008; Revised March 2, 2009; Accepted March 9, 2009
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 Chd7Gt/+ 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.