Open AccessGenomic architecture of Shh dependent cochlear morphogenesis
Author(s) -
Victor Muthu,
Alex M Rohacek,
Yao Yao,
Staci M. Rakowiecki,
Allan H. Brown,
Ying-Tao Zhao,
James Meyers,
Kyoung Jae Won,
Shweta Ramdas,
Christopher D. Brown,
Kevin A. Peterson,
Douglas J. Epstein
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.181339
Subject(s) - biology , sonic hedgehog , otic vesicle , microbiology and biotechnology , morphogenesis , enhancer , cochlear duct , transcriptome , cochlea , inner ear , genetics , gene , signal transduction , transcription factor , gene expression , anatomy , in situ hybridization
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.