Ontogeny of inhibitory neurons in the auditory hindbrain

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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.