Genomic architecture of Shh-dependent cochlear morphogenesis

Research output: Contribution to journalJournal articleResearchpeer-review

  • Victor Muthu
  • Alex M Rohacek
  • Yao Yao
  • Staci M Rakowiecki
  • Alexander S Brown
  • Ying-Tao Zhao
  • James Meyers
  • Won, Kyoung Jae
  • Shweta Ramdas
  • Christopher D Brown
  • Kevin A Peterson
  • Douglas J Epstein

The mammalian cochlea develops from a ventral outgrowth of the otic vesicle in response to Shh signaling. Mouse embryos lacking Shh or its essential signal transduction components display cochlear agenesis; however, a detailed understanding of the transcriptional network mediating this process is unclear. Here, we describe an integrated genomic approach to identify Shh-dependent genes and associated regulatory sequences that promote cochlear duct morphogenesis. A comparative transcriptome analysis of otic vesicles from mouse mutants exhibiting loss (Smoecko ) and gain (Shh-P1) of Shh signaling reveal a set of Shh-responsive genes partitioned into four expression categories in the ventral half of the otic vesicle. This target gene classification scheme provides novel insight into several unanticipated roles for Shh, including priming the cochlear epithelium for subsequent sensory development. We also mapped regions of open chromatin in the inner ear by ATAC-seq that, in combination with Gli2 ChIP-seq, identified inner ear enhancers in the vicinity of Shh-responsive genes. These datasets are useful entry points for deciphering Shh-dependent regulatory mechanisms involved in cochlear duct morphogenesis and establishment of its constituent cell types.

Original languageEnglish
Article number181339
JournalDevelopment (Cambridge, England)
Volume146
Issue number18
Number of pages12
ISSN0950-1991
DOIs
Publication statusPublished - 19 Sep 2019

Bibliographical note

© 2019. Published by The Company of Biologists Ltd.

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