Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development

We report that a putative Notch target gene, hairy-related basic helix-loop-helix (bHLH) transcriptional factor Hey2, is expressed in the cochlear epithelium prior to terminal differentiation. Its expression is subsequently restricted to supporting cells, overlapping with the expression domains of two known Notch target genes, Hairy and enhancer of split homolog genes Hes1 and Hes5. In combination with the loss of Hes1 or Hes5, genetic inactivation of Hey2 leads to increased numbers of mis-patterned inner or outer hair cells, respectively. Surprisingly, the ectopic hair cells in Hey2 mutants are accompanied by ectopic supporting cells. Furthermore, Hey2-/-;Hes1-/- and Hey2-/-;Hes1+/- mutants show a complete penetrance of early embryonic lethality.Our results indicate that Hey2 functions in parallel with Hes1 and Hes5 in patterning the organ of Corti, and interacts genetically with Hes1 for early embryonic development and survival. Our data implicates expansion of the progenitor pool and/or the boundaries of the developing sensory organ to account for patterning defects observed in Hey2 mutants.The organ of Corti consists of four parallel rows of sensory hair cells along the longitudinal axis of the spiraled cochlea. The first row of hair cells from the center, or the medial side, of the cochlea are known as inner hair cells (IHCs). The remaining three rows of hair cells toward the periphery, or the lateral side, of the cochlea are known as outer hair cells (OHCs). Invariably, hair cells are separated from each other by several types of morphologically distinct non-sensory supporting cells. The mosaic cellular arrangement in the organ of Corti allows the tissue to sustain mechanic transduction and to maintain homeostasis required for the function and survival of the organ of Corti.The precise cellular architect of the organ of Corti provides a unique system to examine mechanisms underlying cellular patterning. During development, the precursor cells that give rise to