These studies have direct relevance for improving our understanding of the developmental defects associated with Chd7 deficiency. Precise regulation of gene expression is critical for normal development of most tissues and organs. Chromodomain proteins, characterized by DNA binding and ATP-dependent helicase domains, have poorly understood roles in chromatin remodeling and exert epigenetic influences on gene expression. In humans, haploinsufficiency for CHD7, a member of the third subfamily of chromodomain proteins, causes CHARGE syndrome. CHARGE is a multiple anomaly disorder characterized by ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear anomalies including deafness and vestibular disorders. We generated mice heterozygous for a gene trapped null allele (Chd7Gt/+). These mice exhibit many features similar to human CHARGE phenotypes, including severe inner ear defects and postnatal growth delays. Chd7Gt/+ mice also express a ?-galactosidase reporter in Chd7-positive tissues, and can be used for tracking the fates of Chd7 deficient cells. The clinical features of CHARGE in humans and mice are variable and incompletely penetrant, and the most common developmental malformation in both humans and mice with loss of CHD7 function is semicircular canal dysgenesis or hypoplasia. Inner ear defects with Chd7 deficiency in mice are complex, and include malformations of the semicircular canals and innervation of sensory epithelia. Specific tissues and cell types appear uniquely sensitive to Chd7 dosage, but the cellular Chd7 expression patterns and mechanisms of Chd7 deficiency in cell proliferation, differentiation, and survival are not known. Moreover, CHD7 interacting partners and downstream targets in the ear and neural cells are not characterized. Such knowledge would help guide rational development of therapies for inner ear defects. Our global hypothesis is that CHD7 functions in a transcriptional complex to repress or activate downstream target genes in developing ear and neural tissues. We have three specific aims: (1) Characterize cell proliferation, survival, and differentiation in Chd7 mutant mice, (2) Determine the contributions of CHD7-expressing tissues to inner ear development, and (3) Characterize cultured inner ear and neural stem cells from wildtype and Chd7 mutant embryos, and use them to determine whether CHD7 directly binds the promoters of candidate target genes. Results of proposed experiments will bring novel insights into fundamental processes of chromatin remodeling and transcriptional regulation. Improved understanding of tissue-specific requirements for Chd7 might also improve the diagnosis and treatment of CHARGE-related inner ear and other developmental defects.

Public Health Relevance

This project has direct relevance for understanding the mechanisms of CHD7 deficiency-induced hearing and balance disorders in children and adults with CHARGE syndrome. CHARGE syndrome is a multiple anomaly condition that affects 1 in 10,000 newborn children worldwide. Results of experiments described in this proposal will improve our understanding of genetic and epigenetic factors regulating basic chromatin biology, and their impact on development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009410-05
Application #
8374112
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Freeman, Nancy
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$284,225
Indirect Cost
$90,764
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Van Nostrand, Jeanine L; Brady, Colleen A; Jung, Heiyoun et al. (2014) Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature 514:228-32
Green, Glenn E; Huq, Farhan S; Emery, Sarah B et al. (2014) CHD7 mutations and CHARGE syndrome in semicircular canal dysplasia. Otol Neurotol 35:1466-70
Micucci, Joseph A; Layman, Wanda S; Hurd, Elizabeth A et al. (2014) CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome. Hum Mol Genet 23:434-48
Seeley, Andrea H; Durham, Mark A; Micale, Mark A et al. (2014) Macrocerebellum, epilepsy, intellectual disability, and gut malrotation in a child with a 16q24.1-q24.2 contiguous gene deletion. Am J Med Genet A 164A:2062-8
Sperry, Ethan D; Hurd, Elizabeth A; Durham, Mark A et al. (2014) The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development. Dev Dyn 243:1055-66
Matsui, Toshiyasu; Hongo, Yu; Haizuka, Yoshinori et al. (2013) C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation. Neurosci Lett 548:137-42
Wiggins, Jillian Lee; Bedoyan, Jirair K; Peltier, Scott J et al. (2012) The impact of serotonin transporter (5-HTTLPR) genotype on the development of resting-state functional connectivity in children and adolescents: a preliminary report. Neuroimage 59:2760-70
Layman, Wanda S; Hurd, Elizabeth A; Martin, Donna M (2011) Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome. Hum Mol Genet 20:3138-50
Hurd, Elizabeth A; Adams, Meredith E; Layman, Wanda S et al. (2011) Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome. Hear Res 282:184-95
Skaggs, Kaia; Martin, Donna M; Novitch, Bennett G (2011) Regulation of spinal interneuron development by the Olig-related protein Bhlhb5 and Notch signaling. Development 138:3199-211

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