A jack of all trades: POU3F4 orchestrates diverse transcriptional programs in the developing cochlea

Authors

• CB Wilson
• WM Yau
• R Tycko

Abstract

During inner ear development, otic mesenchyme cells (OMCs) surround and influence the development of many key cochlear structures, including the organ of Corti, spiral ganglion neurons (SGNs), and stria vascularis. We have recently shown that OMCs are not homogenous, but are transcriptionally, spatially, and functionally distinct. Mutations of the OMC-specific transcription factor Pou3f4 are associated with DFNX2, the most common form of X-linked deafness. Loss of Pou3f4 results in numerous cochlear defects, seemingly affecting each of the OMC subpopulations differentially. Here, we hypothesized that the transcriptional changes downstream of POU3F4 in each of the four OMC subpopulations are unique, resulting in the multifaceted cochlear phenotype observed in Pou3f4-KO mice. Indeed, using scRNA-seq and scATAC-seq at embryonic day 15 and postnatal day 7, we show that loss of Pou3f4 leads to an OMC subtype-specific response, with each OMC subtype displaying a unique chromatin landscape and sharing only a few differentially expressed genes. Finally, using cell-cell communication analyses, we describe potential mis-regulated signaling cascades in Pou3f4-KO mice responsible for the defects observed in the surrounding cell types such as the SGNs and stria vascularis. In conclusion, the otic mesenchyme specific transcription factor POU3f4 supports four distinct transcriptional cascades in the regionally and molecularly distinct mesenchymal domains during cochlear development.

Scientific Focus Area: Developmental Biology

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