Ontogeny of inhibitory neurons in the auditory hindbrain
Evolutionary Cell and Developmental Biology (Zoology)
Final Report Abstract
The brainstem comprises the cerebellum, the pons, and the medulla oblongata and harbors an enormous diversity of neuron subtypes. How this diversity is generated is still largely unknown. Here, we investigated the genetic programs involved in the generation of the large variety of inhibitory neurons in the auditory brainstem, especially in the cochlear nucleus complex (CNC). The CNC is the obligatory entry point of the mammalian central auditory system and its complex cytoarchitecture is unique among vertebrates. This holds especially true for the cerebellum-like dorsal cochlear nucleus (DCN) with its layered structure. Cel type-specific marker analysis in combination with a fluorescent Lbx1 reporter mouse provided three major insights into the generation of cell type diversity. i) Two populations of inhibitory neurons exist in the DCN with respect to their developmental program: cells with and without a history of Lbx1 expression. ii) The Lbx1 lineal cell types mainly differ between the DCN and the cerebellum. iii) The Lbx1 lineage contributes also a subpopulation of excitatory granule cells, thereby identifying a genetic heterogeneity previously not reported for this cell type. The function of Lbx1 in the DCN was analyzed in constitutive Lbx1 knockout mice. As these mice die at birth, we focused on embryonal day (E)17. Visual observation as well as cell counts demonstrated that the numbers of Lbx1 lineal cells as well as non-Lbx1 lineal cells were considerably reduced upon Lbx1 deletion. These data suggest a role of Lbx1 for the survival of Lbx1 lineal and non-Lbx1 lineal cells as well as cell autonomous and non-cell autonomous functions of this transcription factor in the auditory brainstem. To identify, which cell types in the DCN were affected by loss of Lbx1, we generated a Ptf1a::Cre; Lbx1fl/fl mouse line which survives postnatally. Cell type analysis revealed partial loss of Lbx1 lineal cells. Contrary to a previous report in the spinal cord, no switch in neurotransmitter phenotype occurred. Finally, we defined the rhombomeric origin of the different cell types in the DCN. Most cell types were of monosegmental origin. Notably, their rhombomeric origin did not provide position identity along the rostrocaudal axis or the dorsomedial-to-ventrolateral tonotopic axis. This contrast the avian auditory system. There, neurons localize according to their birth place in plurisegmental nuclei and tonotopy aligns with the rostrocaudal axis. Our data therefore point to a fundamental ontogenetic difference between mouse and chicken, which might underly different requirements of prehearing activity for formation of tonotopic gradients. In summary, our data support the concept of a complex evolutionary history of the tetrapod auditory system.
Publications
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The Lbx1 lineage differentially contributes to inhibitory cell types of the dorsal cochlear nucleus, a cerebellum‐like structure, and the cerebellum. Journal of Comparative Neurology, 529(11), 3032-3045.
Schinzel, Friedrich; Seyfer, Hannah; Ebbers, Lena & Nothwang, Hans Gerd
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Developmental origin of the cochlear nuclear complex [Dissertation, Carl von Ossietzky Universität Oldenburg, Oldenburg]. Library catalog. (2022)
Schinzel, F.
