Genomic architecture of Shh dependent cochlear morphogenesis

Shh 依赖性耳蜗形态发生的基因组结构

• 批准号: 8629843
• 负责人: DOUGLAS J EPSTEIN
• 金额: $ 41.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629843
• 关键词: Antibodies; Applications Grants; Architecture; Biological Assay; Categories; Cell Cycle; Cell physiology; ChIP-seq; Chromatin; Cochlea; Cochlear duct; Complex; Congenital Abnormality; Coupled; DNA; Data Set; Dependency; Development; Disease; Ear; Embryo; Embryonic Development; Enhancers; Epithelium; Erinaceidae; Event; Exhibits; Functional disorder; Future; Gene Expression; Genes; Genomics; Goals; Hearing; Human; Knock-out; Knockout Mice; Knowledge; Labyrinth; Lead; Location; Logic; Maps; Massive Parallel Sequencing; Medial; Mitotic; Molecular; Molecular Profiling; Morphogenesis; Mus; Otic Vesicle; Pattern; Phenotype; Regulation; Reporter; Role; Sensory; Shapes; Staging; Structure; Testing; Tissues; Transgenic Organisms; Withdrawal; base; cell fate specification; cell type; chromatin immunoprecipitation; deafness; genome-wide; hedgehog signal transduction; human SMO protein; improved; inhibitor/antagonist; inner ear diseases; insight; morphogens; novel; progenitor; public health relevance; research study; response; smoothened signaling pathway; spatiotemporal; transcription factor

The mouse cochlea derives from the ventral extension of the otic vesicle. Over the course of several days during embryonic development, this outgrowth undergoes a complex sequence of morphogenetic changes resulting in its lengthening, coiling and differential patterning into sensory and nonsensory cell types that are essential for hearing (Groves and Fekete, 2012). Congenital malformations of the cochlea often lead to deafness, emphasizing the importance of a thorough understanding of its development (Jackler et al., 1987). We previously described a critical function of the Sonic hedgehog (Shh) signaling pathway in promoting ventral identity within the otic vesicle that is necessary for the subsequent outgrowth of the cochlear duct (Riccomagno et al., 2002; Bok et al., 2007b; Brown and Epstein, 2011). Mouse embryos lacking Shh, or carrying an ear conditional knockout of Smoothened (Smoecko), an essential Shh signal transduction component, exhibit cochlear agenesis. We also classified several transcription factors with key roles in cochlear development as either transcriptional targets (Pax2, Otx2, Gata3) or effectors (Gli2, Gli3) of Shh signaling within the ventral otic epithelium. However, despite these advances, a detailed understanding of the mechanism by which Shh dependent transcription factors promote cochlear duct outgrowth remains unclear, primarily since the genes acting downstream in this transcriptional cascade have yet to be determined. To identify novel targets of Shh signaling we compared the genome-wide expression profiles of control and Smoecko inner ears at E11.5, when the cochlea anlage is evident, and uncovered an intriguing set of Shh responsive genes with a combination of known and previously uncharacterized roles in cochlear morphogenesis. Interestingly, several of these genes maintain their expression at later stages of development within the prosensory domain of the cochlear duct, raising the possibility that Shh signaling is priming the presumptive sensory epithelium for subsequent steps in its development. We propose to characterize the ventral otic gene set according to the following experimental plan: classify their spatiotemporal patterns of expression and dependency on Shh signaling (Aim 1); decode their cis-regulatory architecture (Aim 2); and assess their functional contribution to cochlear development (Aim 3). The results of these experiments should advance our fundamental understanding of the molecular and cellular mechanisms underlying cochlear morphogenesis and cell fate specification within the inner ear.

小鼠耳蜗由耳囊的腹侧延伸而来。在几个过程中