Conditional overexpression of neuritin in supporting cells (SCs) mitigates hair cell (HC) damage and induces HC regeneration in the adult mouse cochlea after drug-induced ototoxicity.

Hearing loss due to the loss of auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Using neurotrophic factors to induce the regeneration of hair cells (HCs) from adjacent nonsensory supporting cells (SCs) may be a promising strategy to treat hearing loss. Here, we demonstrate that overexpression of neuritin in SCs could mitigate drug-induced HC damage and directly induce HC regeneration from SCs by inhibiting the Notch signaling pathway. Using neuritin conditional knock-in mice, we found that upregulation of neuritin in SCs results in preserved HCs and partial recovery of hearing, inducing the regeneration of HCs from the transdifferentiation of SCs in ears damaged by kanamycin. Furthermore, neuritin overexpression in SCs downregulates the expression levels of Notch receptor Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) protein, two core components of the Notch signaling pathway. These observations confirmed in vitro that in cultured neonatal mouse cochleae, neuritin overexpression in SCs significantly inhibited gentamicin-induced HC damage and induced regeneration of HCs from the transdifferentiation of SCs, and that these effects were eliminated by adding the Notch ligand Jagged-1. These findings may provide a new avenue to stimulate HC regeneration after HC loss and highlight the therapeutic potential of neuritin for sensorineural hearing loss.

A global analysis of CNVs in Chinese indigenous fine-wool sheep populations using whole-genome resequencing.

BACKGROUND: Copy number variation (CNV) is an important source of genetic variation that has a significant influence on phenotypic diversity, economically important traits and the evolution of livestock species. In this study, the genome-wide CNV distribution characteristics of 32 fine-wool sheep from three breeds were analyzed using resequencing. RESULTS: A total of 1,747,604 CNVs were detected in this study, and 7228 CNV regions (CNVR) were obtained after merging overlapping CNVs; these regions accounted for 2.17% of the sheep reference genome. The average length of the CNVRs was 4307.17 bp. "Deletion" events took place more frequently than "duplication" or "both" events. The CNVRs obtained overlapped with previously reported sheep CNVRs to variable extents (4.39-55.46%). Functional enrichment analysis showed that the CNVR-harboring genes were mainly involved in sensory perception systems, nutrient metabolism processes, and growth and development processes. Furthermore, 1855 of the CNVRs were associated with 166 quantitative trait loci (QTL), including milk QTLs, carcass QTLs, and health-related QTLs, among others. In addition, the 32 fine-wool sheep were divided into horned and polled groups to analyze for the selective sweep of CNVRs, and it was found that the relaxin family peptide receptor 2 (RXFP2) gene was strongly influenced by selection. CONCLUSIONS: In summary, we constructed a genomic CNV map for Chinese indigenous fine-wool sheep using resequencing, thereby providing a valuable genetic variation resource for sheep genome research, which will contribute to the study of complex traits in sheep.