Notch1 and Notch2 receptors mediate the prosensory functions of the Notch ligand Jagged1 in the mammalian cochlea

Mechanosensory hair cells in the cochlea of the inner ear are essential for sound detection. Previous studies have shown that loss of the Notch ligand Jagged1 (JAG1) disrupts maintenance of prosensory progenitors, from which hair cells and their surrounding supporting cells derive. However, the molecular and cellular mechanisms by which JAG1 regulates prosensory progenitor maintenance are poorly understood, and the Notch receptors that mediate this function in the developing cochlea remain unknown. To address this, we generated Jag1 conditional knockout mice and characterized their prosensory deficits using transcriptomic and phenotypic analyses. We show that JAG1 loss abolishes prosensory expression of CDKN1B (p27Kip1) and reduces expression of essential neurotrophic factors, thereby disrupting the stereotyped pattern of cell-cycle exit and innervation within the prosensory domain. Furthermore, conditional knockout of Notch1 and Notch2 (Notch1/2) receptors in supporting cells phenocopied the Jag1 deletion phenotype, showing both a severe reduction in outer hair cell formation and a disrupted pattern of cell-cycle exit and innervation, thereby confirming their essential roles in mediating the prosensory functions of JAG1.