MATH 1 AND CNS AND PNS DEVELOPMENT

在果蝇中，atonal编码一种基本的螺旋-环-螺旋（bHLH）蛋白，这对chordotonal器官（本体感觉、平衡和听觉的感觉器官）的发育至关重要。小鼠无调性同源物1 （Math1）在后脑、背神经管、内耳、默克尔细胞和关节中表达。小鼠基因靶向研究表明，Mah1对小脑颗粒神经元和内耳毛细胞的形成至关重要。此外，由于无法呼吸，Math1可能在出生后不久就会死亡。为了研究Math1对参与呼吸控制的神经元分化的影响，我们将评估Math1缺失胚胎中呼吸回路的神经生理完整性，绘制表达Math1缺失新生儿的胚胎脑干神经元的命运图，我们还将定位到Math1位点，以确定表型的哪些方面可以被拯救。完全恢复将确定bHLH结构域是Math1功能的中介；部分拯救将表明该蛋白质的其他部分对哺乳动物是必需的。这些数据将有助于进一步分析脑干、小脑和内耳毛细胞发育过程中的分子相互作用，并有助于理解小脑异常、耳聋、平衡障碍和新生儿呼吸功能障碍。

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.