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INNER EAR EMBRYOGENESIS: GENETIC AND ENVIRONMENTAL DETERMINANTS
Sulik, K. K., W. C. Dunty, AND R M. Zucker. INNER EAR EMBRYOGENESIS: GENETIC AND ENVIRONMENTAL DETERMINANTS. Presented at David Smith Conference on Malformations and Morphogenesis, Vancouver BC, Canada, August 7-11, 2003.
The anatomy and developmental molecular genetics of the inner ear from establishment of the otic placode to formation of the definitive cochlea and vestibular apparatus will be reviewed and the complex 3-D structural changes that shape the developing inner ear will be illustrated in paint-filled specimens.and scanning electron micrographs. Both the cochlear and vestibular portions of the inner ear contain hair cells. A total of 6 sensory patches are present; the Organ of Corti in the cochlea, 3 cristae associated with the semicircular canals, and a saccular and utricular macula. Patterning of sensory and supporting cells within these patches appears to result from lateral inhibition, a process by which a cell that adopts a certain fate inhibits its neighbors from adopting the same cell fate. The sensory neurons and the primary neurons with which they connect appear to be clonally related, i.e. they are derived from common progenitors in the otic epithelium. These cells may be identified by BMP4 expression and by their relative density of nuclear Prox1 protein (a homeobox transcription factor). They are located in an anteroventral to posteromedial band of otic vesicle epithelium. This is also the location of a significant amount of programmed cell death as can be visualized in reconstructed confocal images of LysoTracker Red-stained mouse embryos. Fibroblast growth factors (Fgf 3 and 10) eminating from both the hindbrain and adjacent mesenchyme are required for otic placode induction. Otic vesicles normally form next to rhombomeres (r) 5 and 6 of the hindbrain. Mutations that disrupt patterning of the hindbrain commonly also affect inner ear development. Of particular note for the current review are the kreisler mutation (a mutation in the Krm1 gene) and Hoxa1 deficiency, both of which result in absence of r5 and dysmorphic inner ears. Additionally, mutations affecting retinoic acid signaling, esp. Raldh2 knockout, will be described. Importantly, retinoic acid can rescue the inner ears of Hoxa1 knockout mice; it regulates BMP4 signaling, and is required for normal Fgf3 expression. Additionally, diminished retinoic acid signaling due to competitive inhibition of its synthesis from retinol via alcohol dehydrogenase is hypothesized to be a basis for alcohol-induced dysmorphogenesis. Noteworthy is alcohol-induced excessive cell death in a discrete pattern within the developing otic vesicle in mouse embryos exposed to high concentrations of alcohol at a time corresponding to the fourth week of human gestation. The location of the dying cells corresponds to that of the sensorineural progenitors, prediciting subsequent sensorineural hearing loss. Although more extensive analyses of human populations are needed, sensorineural hearing loss has been reported in as many as 25% of individuals with full-blown FAS.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
REPRODUCTIVE TOXICOLOGY DIVISION
GAMETE AND EARLY EMBRYO BIOLOGY BRANCH