A Cross-Species Single-Cell Atlas Reveals Conserved Regulatory Networks and Candidate Hearing Loss Genes in the Cochlea

Background: The cochlea is a specialized sensory organ essential for hearing. To elucidate its cellular and molecular architecture and prioritize candidate genes associated with hearing loss (HL), we constructed a cross-species single-cell transcriptomic atlas of human fetal and postnatal mouse cochleae. Methods: We integrated single-cell and single-nucleus RNA sequencing datasets from human fetal cochleae and postnatal mouse cochleae to build a comprehensive cross-species single-cell transcriptomic atlas. Cell-type annotation, transcriptional regulator analysis, intercellular communication, and disease phenotypes were performed to dissect the cochlear cellular landscape, regulatory programs, and potential HL gene candidates. Results: A total of 19 major cochlear cell types were identified in both species, with conserved cellular composition and transcriptional programs. Comparative analysis revealed strong transcriptional conservation between matched human and mouse cell types, particularly in supporting, schwann cells and hair cells. Cell–cell communication analysis revealed conserved signaling pathways, including the BDNF-NTRK2 axis, potentially involved in cochlear development and auditory function. Regulatory network inference uncovered conserved and previously undercharacterized transcription factors, such as SKOR1, RFX2, and PAX2, predicted to be associated with hair cell identity and function. We further defined a conserved gene module of 3138 hair cell-enriched genes, from which 24 candidate HL-associated genes (e.g., ATP8B1, BDNF, and SOD1) were prioritized through integration with human disease databases and mouse auditory phenotype annotations. Conclusions: This study provides a high-resolution cross-species cochlear atlas, revealing conserved molecular programs and candidate HL-associated genes, offering valuable insights into auditory biology and potential avenues for further investigation.