期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：28
DOI：10.1073/pnas.2118938119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Responsible for the sense of hearing and balance, the inner ear is critically important for communication with the environment. In humans, developmental malformations of the ear have lifelong consequences, while age-related hearing defects affect a large proportion of the population. However, many of the underlying genetic mechanisms remain unknown, and no regenerative strategies are available. Here, we characterize the transcriptional and regulatory landscape of ear progenitors, providing unprecedented detail on the molecular aspects of early ear development. We identify the transcription factor Sox8 as a key regulator that initiates the ear program including ear neurogenesis. Our findings not only elucidate how cell fate decisions are regulated in the embryo but can also inform reprogramming and regenerative strategies for the ear.
The vertebrate inner ear arises from a pool of progenitors with the potential to contribute to all the sense organs and cranial ganglia in the head. Here, we explore the molecular mechanisms that control ear specification from these precursors. Using a multiomics approach combined with loss-of-function experiments, we identify a core transcriptional circuit that imparts ear identity, along with a genome-wide characterization of noncoding elements that integrate this information. This analysis places the transcription factor Sox8 at the top of the ear determination network. Introducing Sox8 into the cranial ectoderm not only converts non-ear cells into ear progenitors but also activates the cellular programs for ear morphogenesis and neurogenesis. Thus, Sox8 has the unique ability to remodel transcriptional networks in the cranial ectoderm toward ear identity.
