Genomic architecture of Shh-dependent cochlear morphogenesis

TY - JOUR

T1 - Genomic architecture of Shh-dependent cochlear morphogenesis

AU - Muthu, Victor

AU - Rohacek, Alex M

AU - Yao, Yao

AU - Rakowiecki, Staci M

AU - Brown, Alexander S

AU - Zhao, Ying-Tao

AU - Meyers, James

AU - Won, Kyoung-Jae

AU - Ramdas, Shweta

AU - Brown, Christopher D

AU - Peterson, Kevin A

AU - Epstein, Douglas J

N1 - © 2019. Published by The Company of Biologists Ltd.

PY - 2019/9/19

Y1 - 2019/9/19

N2 - 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.

AB - 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.

U2 - 10.1242/dev.181339

DO - 10.1242/dev.181339

M3 - Journal article

C2 - 31488567

SN - 0950-1991

VL - 146

JO - Development

JF - Development

IS - 18

M1 - 181339

ER -