Ontogeny of inhibitory neurons in the auditory hindbrain

对任何多细胞生物来说，发育组织内独特的细胞命运是基本的。哺乳动物后脑有许多不同的神经元群，它们共同构成了耳蜗核复合体（CNC）、上橄榄树复合体（SOC）和外侧小网膜（LL）。这些细胞中有相当一部分是抑制性神经元，它们作为中间神经元出现，甚至形成单独的细胞核。这些神经元在频谱和时序分析、声源定位和听流分离中起着关键作用。小鼠遗传分析显示，CNC的抑制神经元为Ptf1a+直系细胞，而SOC中的许多抑制神经元为En1+直系细胞。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神经元群，它们的个体发育仍然未知。为了缩小这些差距，我们将描述Lbx1+和Lhx1+谱系对听觉后脑的贡献。这两种转录因子都与大脑其他区域的Ptf1a+谱系有关。初步数据表明，在CNC中，许多（如果不是全部的话）抑制性神经元都是Lbx1+。在SOC中进一步观察到Lbx1+直线型细胞，对比该结构中Ptf1a+直线型细胞的缺失。在这个项目中，我们将首先定义Lbx1+谱系对听觉后脑的精确贡献。其次，为了确定这种转录因子的功能，我们将分析Lbx1-/-小鼠在细胞命运、细胞丢失和异常轴突寻路方面的开关。此外，将通过比较野生型和Lbx1-/-小鼠中已知Lbx1下游作用因子的表达模式，确定听觉后脑中Lbx1依赖的遗传程序。第三，我们将确定Lhx1+直系细胞对听觉后脑的贡献。最后，我们将使用获得的数据来解决听觉后脑的进化，这是该领域的另一个突出问题。目前的观点认为，哺乳动物的听觉后脑核代表了进化的新颖性，而鸟类的听觉后脑核反映了趋同进化产生的同源结构。这个过程可以通过招募不同或相似的基因程序来实现。后者将支持进化过程中发育限制的概念。为了解决这个问题，我们将在鸡中描述Ptf1a/Lbx1相关基因调控网络，因为Ptf1a+直系细胞也有助于禽类抑制性听觉神经元。总之，这种系统的方法将产生关于四足动物抑制性听觉神经元个体发生的全面知识。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.