title: Limited inner ear morphogenesis and neurosensory development are possible in the absence of GATA3.
abstract: Haploinsufficiency of Gata3 causes hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome in mice and humans. Gata3 null mutation leads to early lethality around embryonic day (E)11.5, but catecholamine precursor administration can rescue Gata3 null mutants to E16.5. At E11.5, GATA3 deficiency results in the development of an empty otocyst with an endolymphatic duct. However, using rescued mice we found that some morphogenesis and neurosensory development is possible in the ear without Gata3. Extending previous studies, we find that at E16.5, Gata3 mutant inner ears can undergo partial morphogenesis and develop an endolymphatic duct, a utricular and saccular recess, and a shortened cochlear duct. In addition to the obvious morphogenic aberrations, these studies demonstrate that a subset of neurons develop and connect a fragmented sensory patch of MYO7A-positive hair cells to the vestibular nuclei of the brainstem. In situ hybridization studies reveal altered expression of several transcription factors relevant to ear development and we hypothesize that this may relate to the observed dysmorphia and restricted neurosensory development. While a cochlear duct can form, there is no concurrent cochlear neurosensory development, observations consistent with specific hearing defects encountered by HDR patients and mice with Gata3-associated expression alterations. Gata3 null mutant phenocopies the otic maldevelopment (cochlear duct formation in the absence of neurosensory development) seen in Foxg1cre mediated conditional deletion of microRNA processing enzyme, Dicer1. Finally, while GATA3 is expressed in the developing vestibulo-cochlear efferent (VCE) neurons, and its absence in the null mutants disrupts VCE projections to the ear, loss of GATA3 does not affect VCE progenitor cell migration.
authors.affiliation: Department of Biology, University of Iowa, Iowa, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duncan
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.forename: James D
authors.initials: JD
authors.lastname: Engel
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000008:administration & dosage / Q000494:pharmacology; D002465:Cell Movement; D003053:Cochlear Duct / Q000002:abnormalities; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology* / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018069:Hair Cells, Vestibular / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D009490:Neurosecretory Systems / Q000196:embryology* / Q000378:metabolism*; D000159:Vestibulocochlear Nerve / Q000378:metabolism
chemical_list: D002395:Catecholamines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009218:Myosins