EBF1 Regulates Sensory Development in the Mammalian Cochlea

Abstract

Hair cell damage is a leading cause of sensorineural hearing loss. Unlike non-mammalian vertebrates, which regenerate hair cells throughout their lives, mammals lose the ability to spontaneously generate cochlear hair cells within the first postnatal week. Understanding the developmental programs that drive sensory development is essential for the design of effective regenerative therapeutics to fight hearing loss. However, large gaps remain in our understanding of the signals that direct cochlear development. Recent work in the Bermingham-McDonogh lab identified enrichment of EBF (Early B cell Factor) consensus DNA-binding motifs in the open chromatin of prosensory cells collected from embryonic mouse cochleae. Although Ebf genes are often expressed in overlapping patterns, this appears to not be the case for the cochlea. Single cell RNA-seq analysis revealed that Ebf1 shows strong expression in the developing cochlear epithelium, whereas Ebf2-4 show little to no expression. To determine how loss of EBF1 affects cochlear development, I generated conditional knockout mouse models. The work presented in this dissertation characterizes the role of EBF1 in cochlear development. First, Ebf1 conditional knockout mouse phenotypes were examined, with particular attention to how Ebf1 excision affects cochlear patterning, prosensory proliferation, sensory differentiation and maturation, and hearing. Second, a multiomic approach that combines single nucleus RNA-seq and single nucleus ATAC-seq into a single workflow was used to identify EBF1’s roles as a transcriptional activator and repressor within a regulatory network. This work provides valuable insight into how EBF1 regulates cell fate and proliferation to restrict sensory development in the mammalian cochlea, and in turn, offers valuable insight into a novel target for future regenerative strategies.