MATH 1 AND CNS AND PNS DEVELOPMENT

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In Drosophila, atonal encodes a basic helix-loop-helix (bHLH) protein essential for the development of chordotonal organs (sensory organs for proprioception, balance and audition). The mouse atonal homolog 1 (Math1) is expressed in the hindbrain, dorsal neural tube, inner ear, Merkel cells, and joints. Gene targeting in mice revealed that Mah1 is essential for the genesis of cerebellar granule neurons and inner ear hair cells. Furthermore, Math1 null nice die shortly after birth because of inability to breathe. To investigate the influence of Math1 on the differentiation of neurons involved in respiratory control, we will assess the neurophysiological integrity of the respiratory circuitry in Math1 null embryos, fate-map embryonic brainstem neurons that express Math1 null newborns die quickly, we will also target atonal into the Math1 locus to ascertain which facets of the phenotype can be rescued. Complete rescue will identify the bHLH domain as the mediator of Math1 function; partial rescue will indicate that other portions of the protein are necessary in the mammal. These data will allow future analysis of molecular interactions in the development of the brainstem, cerebellum and inner ear hair cells, with ramifications for understanding cerebellar anomalies, deafness, balance disorders, and neonatal breathing dysfunctions.