PRDM16 expression and function in mammalian cochlear development.

Abstract

PR domain containing 16 (PRDM16) is a key transcriptional regulator in the development of craniofacial, adipose, and neural tissues. Our lab identified PRDM16 expression in the epithelial cells of the Kölliker's organ (KO) that starts at ~E13.5 and is maintained until KO disappearance. A transgenic mouse model that carries a gene trap null allele of Prdm16 (Prdm16cGT ) was used to characterize the impact of Prdm16 loss on cochlear development. At P0 Prdm16cGT null cochlea exhibited hypoplastic KO, shortened cochlear duct, increased density of hair cells (HCs) and supporting cells (SCs) in the apical turn as well as multiple isolated ectopic HCs within the KO domain. KO epithelial cells proliferation rate was reduced in the apical turn of the developing Prdm16cGT null cochlea vs controls. Bulk RNA sequencing of cochlear duct cells at E14.5 followed by quantitative real time PCR and mRNA Fluorescence in-situ hybridization (FISH) validation identified differentially expressed genes in Prdm16cGT null vs littermate control cochleae. Upregulated genes at E14.5 included Fgf20, as well as several Notch pathway genes (Lfng, Hes1, and Jag1). This study characterizes Prdm16 expression during cochlear development and establishes its requirement for KO development.