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Neurod1 regulates survival and formation of connections in mouse ear and brain

机译:Neurod1调节小鼠耳朵和大脑的存活和连接的形成

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The developing sensory neurons of the mammalian ear require two sequentially activated bHLH genes, Neurog1 and Neurod1, for their development. Neurons never develop in Neurog1 null mice, and most neurons die in Neurod1 null mutants, a gene upregulated by Neurog1. The surviving neurons of Neurod1 null mice are incompletely characterized in postnatal mice because of the early lethality of mutants and the possible compromising effect of the absence of insulin on peripheral neuropathies. Using Tg(Pax2-cre), we have generated a conditional deletion of floxed Neurod1 for the ear; this mouse is viable and allows us to investigate ear innervation defects of Neurod1 absence only in the ear. We have compared the defects in embryos and show an ear phenotype in conditional Neurod1 null mice comparable with the systemic Neurod1 null mouse. By studying postnatal animals, we show that Neurod1 not only is necessary for the survival of most spiral and many vestibular neurons, but is also essential for a segregated central projection of vestibular and cochlear afferents. In the absence of Neurod1 in the ear, vestibular and cochlear afferents enter the cochlear nucleus as a single mixed nerve. Neurites coming from vestibular and cochlear sensory epithelia project centrally to both cochlear and vestibular nuclei, in addition to their designated target projections. The peripheral innervation of the remaining sensory neurons is disorganized and shows collaterals of single neurons projecting to multiple endorgans, displaying no tonotopic organization of the organ of Corti or the cochlear nucleus. Pending elucidation of the molecular details for these Neurod1 functions, these data demonstrate that Neurod1 is not only a major factor for the survival of neurons but is crucial for the development of normal ear connections, both in the ear and in the central nervous system.
机译:哺乳动物耳朵正在发育的感觉神经元需要两个顺序激活的bHLH基因Neurog1和Neurod1才能发育。神经元从未在Neurog1 null小鼠中发育,大多数神经元在Neurod1 null突变体(Neurog1上调的基因)中死亡。 Neurod1 null小鼠的存活神经元在出生后小鼠中的特征不完全,这是因为突变体的早期致死性以及胰岛素缺乏对周围神经病的可能损害作用。使用Tg(Pax2-cre),我们已经产生了有条件的耳朵绒毛Neurod1缺失;这种小鼠是可行的,并允许我们仅在耳朵中研究Neurod1缺失的耳朵神经支配缺陷。我们已经比较了胚胎中的缺陷,并显示了与系统性Neurod1无效小鼠相当的条件性Neurod1无效小鼠的耳表型。通过研究产后动物,我们显示Neurod1不仅对于大多数螺旋形和许多前庭神经元的存活是必需的,而且对于前庭和耳蜗传入中心的分离中央投影也是必不可少的。在耳朵没有Neurod1的情况下,前庭和耳蜗传入神经作为单个混合神经进入耳蜗核。来自前庭和耳蜗感觉上皮的神经突,除了指定的目标投影外,还集中突出到耳蜗和前庭核。其余感觉神经元的周围神经支配是混乱的,显示出单个神经元的侧支伸向多个内脏,而没有皮质醇或耳蜗核的异位组织。在对这些Neurod1功能的分子细节进行阐明之前,这些数据表明Neurod1不仅是神经元存活的主要因素,而且对于在耳朵和中枢神经系统中正常的耳朵连接的发展也至关重要。

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