title: CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome.
abstract: CHARGE syndrome is a multiple congenital anomaly disorder that leads to life-threatening birth defects, such as choanal atresia and cardiac malformations as well as multiple sensory impairments, that affect hearing, vision, olfaction and balance. CHARGE is caused by heterozygous mutations in CHD7, which encodes an ATP-dependent chromatin remodeling enzyme. Identification of the mechanisms underlying neurological and sensory defects in CHARGE is a first step toward developing treatments for CHARGE individuals. Here, we used mouse models of Chd7 deficiency to explore the function of CHD7 in the development of the subventricular zone (SVZ) neural stem cell niche and inner ear, structures that are important for olfactory bulb neurogenesis and hearing and balance, respectively. We found that loss of Chd7 results in cell-autonomous proliferative, neurogenic and self-renewal defects in the perinatal and mature mouse SVZ stem cell niche. Modulation of retinoic acid (RA) signaling prevented in vivo inner ear and in vitro neural stem cell defects caused by Chd7 deficiency. Our findings demonstrate critical, cooperative roles for RA and CHD7 in SVZ neural stem cell function and inner ear development, suggesting that altered RA signaling may be an effective method for treating Chd7 deficiency.
authors.affiliation: Department of Biological Chemistry.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Micucci
authors.forename: Wanda S
authors.initials: WS
authors.lastname: Layman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hurd
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Sperry
authors.forename: Sophia F
authors.initials: SF
authors.lastname: Frank
authors.forename: Mark A
authors.initials: MA
authors.lastname: Durham
authors.forename: Donald L
authors.initials: DL
authors.lastname: Swiderski
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Skidmore
authors.forename: Peter C
authors.initials: PC
authors.lastname: Scacheri
authors.forename: Yehoash
authors.initials: Y
authors.lastname: Raphael
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D058747:CHARGE Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002552:Cerebral Ventricles / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D009830:Olfactory Bulb / Q000473:pathology; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D014212:Tretinoin
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