Ontogeny of inhibitory neurons in the auditory hindbrain

发育组织中独特细胞命运的规范是任何多细胞生物体的基础。哺乳动物的后脑包含许多不同的神经元群，它们共同构成耳蜗核复合体（CNC）、上级橄榄复合体（SOC）和外侧丘系（LL）。这些细胞中有相当数量是抑制性神经元，它们作为中间神经元出现，甚至形成单独的细胞核。这些神经元在分析频谱和时间，声源的位置和听觉流分离中起着关键作用。在小鼠中的遗传分析显示，CNC的抑制性神经元是Ptf 1a+线性细胞，并且SOC中的许多抑制性神经元是En 1+线性细胞。然而，分子伴侣和下游因素仍有待研究。此外，对于听觉后脑中的一些抑制性神经元群体，它们的个体发育仍然是未知的。为了缩小这些差距，我们将描述Lbx 1+和Lhx 1+谱系对听觉后脑的贡献。这两种转录因子都与其他脑区的Ptf 1a+谱系相关。初步数据表明，CNC中的许多（如果不是全部）抑制性神经元是Lbx 1+。在SOC中观察到进一步的Lbx 1+线性细胞，与此结构中Ptf 1a+线性细胞的缺失形成对比。在这个项目中，我们将首先定义Lbx 1+谱系对听觉后脑的精确贡献。第二，为了确定该转录因子的功能，将分析Lbx 1-/-小鼠在细胞命运、细胞丢失和异常轴突寻路中的开关。此外，Lbx 1依赖的听觉后脑的遗传程序将通过比较野生型和Lbx 1-/-小鼠中已知的Lbx 1下游作用因子的表达模式来确定。第三，我们将确定Lhx 1+线性细胞的听觉后脑的贡献。最后，我们将使用所获得的数据来解决听觉后脑的进化，这是该领域的另一个悬而未决的问题。目前的观点认为，哺乳动物的听觉后脑核团代表进化的新奇性，它们在鸟类中功能等同的核团反映了趋同进化产生的同质结构。这个过程可以通过招募不同或相似的遗传程序来发生。后者将支持进化过程中的发展制约的概念。为了解决这个问题，我们将描述Ptf 1a/Lbx 1相关的基因调控网络也在鸡，Ptf 1a+线性细胞有助于鸟类抑制性听觉神经元以及。总而言之，这种系统的方法将产生全面的知识，关于抑制性听觉神经元的个体发育跨越四足动物。因此，它也将为神经系统的进化发育过程提供新的见解。

The specification of unique cell fates within the developing tissue is fundamental for any multicellular organism. The mammalian hindbrain harbors many different neuronal populations, which together constitute the cochlear nucleus complex (CNC), the superior olivary complex (SOC), and the lateral lemniscus (LL). A substantial number of these cells are inhibitory neurons that occur as interneurons or form even separate nuclei. These neurons play pivotal roles in the analysis of spectrum and timing, location of sound sources, and auditory stream segregation. Genetic analyses in mice revealed that inhibitory neurons of the CNC are Ptf1a+ lineal cells and many inhibitory neurons in the SOC are En1+ lineal cells. However, molecular partners and downstream factors remain to be investigated. Furthermore, for some inhibitory neuronal populations in the auditory hindbrain, their ontogeny is still unknown. To close these gaps, we will characterize the contribution of the Lbx1+ and Lhx1+ lineages to the auditory hindbrain. Both transcription factors have been associated with the Ptf1a+ lineage in other brain regions. Preliminary data indicate that many if not all inhibitory neurons in the CNC are Lbx1+. Further Lbx1+ lineal cells were observed in the SOC, contrasting the absence of Ptf1a+ lineal cells in this structure. Within this project, we will first define the precise contribution of the Lbx1+ lineage to the auditory hindbrain. Second, to define the function of this transcription factor, Lbx1-/- mice will be analyzed with respect to switches in cell fate, cell loss, and abnormal axonal pathfinding. Furthermore, the Lbx1 dependent genetic program in the auditory hindbrain will be identified by comparing the expression pattern of known Lbx1 downstream acting factors in wildtype and Lbx1-/- mice. Third, we will determine the contribution of Lhx1+ lineal cells to the auditory hindbrain. Finally, we will use the obtained data to address the evolution of the auditory hindbrain, another outstanding question in the field. Current view holds that mammalian auditory hindbrain nuclei represent evolutionary novelties and that their functionally equivalent nuclei in birds reflect homoplasious structures, generated by convergent evolution. This process can occur by recruitment of distinct or similar genetic programs. The latter would support the concept of developmental constraints within evolutionary processes. To address this issue, we will characterize the Ptf1a/Lbx1 associated gene regulatory network also in chicken, as Ptf1a+ lineal cells contribute to avian inhibitory auditory neurons as well. Altogether, this systematic approach will generate comprehensive knowledge concerning the ontogeny of inhibitory auditory neurons across tetrapods. Thereby it will also provide new insight into evolutionary developmental processes in the nervous system.