Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers
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Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers Iva Filova 1 & Martina Dvorakova 1 & Romana Bohuslavova 1 & Adam Pavlinek 1 & Karen L. Elliott 2 & Simona Vochyanova 1 & Bernd Fritzsch 2 & Gabriela Pavlinkova 1 Received: 26 July 2020 / Accepted: 24 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Ear development requires the transcription factors ATOH1 for hair cell differentiation and NEUROD1 for sensory neuron development. In addition, NEUROD1 negatively regulates Atoh1 gene expression. As we previously showed that deletion of the Neurod1 gene in the cochlea results in axon guidance defects and excessive peripheral innervation of the sensory epithelium, we hypothesized that some of the innervation defects may be a result of abnormalities in NEUROD1 and ATOH1 interactions. To characterize the interdependency of ATOH1 and NEUROD1 in inner ear development, we generated a new Atoh1/Neurod1 double null conditional deletion mutant. Through careful comparison of the effects of single Atoh1 or Neurod1 gene deletion with combined double Atoh1 and Neurod1 deletion, we demonstrate that NEUROD1-ATOH1 interactions are not important for the Neurod1 null innervation phenotype. We report that neurons lacking Neurod1 can innervate the flat epithelium without any sensory hair cells or supporting cells left after Atoh1 deletion, indicating that neurons with Neurod1 deletion do not require the presence of hair cells for axon growth. Moreover, transcriptome analysis identified genes encoding axon guidance and neurite growth molecules that are dysregulated in the Neurod1 deletion mutant. Taken together, we demonstrate that much of the projections of NEUROD1-deprived inner ear sensory neurons are regulated cell-autonomously. Keywords bHLH genes . Ear neurosensory development . Neuronal differentiation . Central projections . Axon guidance
Introduction Ear morphogenesis is governed by a gene regulatory network formed by the temporal and spatial integration of signaling pathways and transcription factors. Neuronal, sensory, and non-sensory cell fates are defined by regulatory patterns mediated by local interactions (Delta-Notch); morphogen gradients of WNT, FGF, SHH, and BMP signaling [1]; and
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02092-0) contains supplementary material, which is available to authorized users. * Bernd Fritzsch [email protected] * Gabriela Pavlinkova [email protected] 1
Institute of Biotechnology of the Czech Academy of Sciences, 25250 Vestec, Czechia
2
Department of Biology, University of Iowa, Iowa City, IA 52242-1324, USA
regionally expressed transcription factors (EYA1, SIX1, GATA3, PAX2, SOX2 [2–5]). The initial neurosensory domain is transformed into distinct cell types by the expression of basic helix-loop-helix (bHLH) transcription factors (ATOH1, NEUROGENIN1, and NEUROD1). Inner ear neuronal development depends on NEUROGENIN1 (NEUROG1) and NEUROD1 fo
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