Evolutionary development of excitatory projection neurons in tetrapod sound localization circuits

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Sound localization is a fundamental aspect in hearing. In tetrapods (amphibians, reptiles, birds, and mammals), processing of cues for sound localization first occurs in neuronal circuits within the hindbrain. Some of the most important questions regarding these circuits relate to their development and evolution. Eutherian mammals feature three sound localization circuits in the hindbrain. In all of them, the major projection neurons are VGluT2+ cells. Based on common embryonic origin, cell morphology, as well as innervation and projection patterns, I recently proposed them to represent serial homologs with modifications. Their molecular relationship and the genetic program governing their differentiation are currently unknown. Concerning the evolution of sound localization circuits across tetrapods, the prevailing view is that they have arisen independently and represent examples of convergent evolution. This is based on anatomical and physiological differences between these circuits and the independent evolution of tympanic ears in vertebrate groups. Yet, recent cell fate analyses suggest that at least some mammalian and avian neurons of sound localization circuits, including VGluT2+ cells, are derived from the same transcription factor lineages. Thus, no simple statements concerning shared ancestry or convergence can yet be made.Here, we will deploy comparative molecular developmental biology and bioinformatics to assess development and evolution of tetrapod sound localization circuits. In a first step, transcriptome analysis of the different VGluT2+ neuronal populations in the mouse auditory hindbrain will be performed by RNA-seq at P0 and P25. P0 represents an intermediate regulatory state and P25 terminal differentiation. Expression profiles will be compared with another VGluT2+ population of independent origin in the auditory hindbrain. Subsequently, bioinformatics analyses will be applied to the data sets to construct tentative gene regulatory networks (GRNs). These data will i) inform our understanding of the genetic programs underlying development of mammalian sound localization circuits, ii) identify the differentiation programs that drive serial homologs towards distinct cell functions, iii) define the molecular signatures of these homologs, and iv) define their genetic relationship. In a final step, a comprehensive comparative characterization of key GRN components in mouse and chicken will be performed by extensive RNA in situ hybridization. The resulting expression maps (the first of this kind) of GRN components across tetrapod sound localization circuits will serve as an essential molecular data-driven framework for assessing and dissecting their evolution. Altogether, we will apply a fundamental concept in evolutionary developmental biology by probing GRNs operating in sound localization circuits of mammals and birds. This will provide key information concerning the evolutionary development of central auditory structures.