Prox1 interacts with Atoh1 and Gfi1, and regulates cellular differentiation in the inner ear sensory epithelia

Abstract

Inner ear hair cells and supporting cells arise from common precursors and, in mammals, do not show phenotypic conversion. Here, we studied the role of the homeodomain transcription factor Prox1 in the inner ear sensory epithelia. Adenoviral-mediated Prox1 transduction into hair cells in explant cultures led to strong repression of Atoh1 and Gfi1, two transcription factors critical for hair cell differentiation and survival. Luciferase assays showed that Prox1 can repress transcriptional activity of Gfi1 independently of Atoh1. Prox1 transduction into cochlear outer hair cells resulted in degeneration of these cells, consistent with the known phenotype of Gfi1-deficient mice. These results together with the widespread expression of endogenous Prox1 within the population of inner ear supporting cells point to the role for Prox1 in antagonizing the hair cell phenotype in these non-sensory cells. Further, in vivo analyses of hair cells from Gfi1-deficient mice suggest that the cyclin-dependent kinase inhibitor p57(Kip2) mediates the differentiation- and survival-promoting functions of Gfi1. These data reveal novel gene interactions and show that these interactions regulate cellular differentiation within the inner ear sensory epithelia. The data point to the tight regulation of phenotypic characteristics of hair cells and supporting cells.

Atoh1 in sensory hair cell development: constraints and cofactors

“…In one report that examines both proteins, Atoh1 and Gfi1 were found to be co-expressed in cochlear inner hair cells as early as E15.0, and in outer hair cells by E15.5 (76). Transcriptome analyses also support their coexpression during later stages of differentiation (77).…”

“…In the cochlea, the onset of Pou4f3 expression occurs at E14.5, prior to Gfi1 but in a similar basal-to-apical gradient (21,46,76). Moreover, Gfi1 expression is affected in Pou4f3 mutant mice (60).…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Despite a high protein sequence similarity between Prospero and Prox1, the amino acid motif responsible for this asymmetric segregation of Prospero seems not present in Prox1 , and asymmetric segregation of Prox1 has not been reported to date. Like Prospero, Prox1 is also expressed in many other organs, such as the liver, brain, pancreas, heart, eye lens, ear sensory epithelium, taste bud, and retina (Oliver et al 1993;SosaPineda et al 2000;Govindarajan and Overbeek 2001;Miura et al 2003;Bermingham-McDonogh et al 2006;Dudas et al 2006;Edqvist et al 2006;Laerm et al 2007;Kirjavainen et al 2008;Risebro et al 2009). Interestingly, the cell-fate-specifying function of Prospero seems to have been inherited by Prox1 and appears to be the common functional theme of Prox1 in such diverse cell types.…”

Transcription Factor-mediated Epigenetic Reprogramming

“…In contrast, expression of Ngn3 in mature hepatocytes induced only insulin expression (but not transdif- (41). An additional example of reprogramming in vivo comes from the inner ear, where the TFs Atoh1 and Prox1, among others, were found to regulate the development of sensory hair cells and supporting cells from a common progenitor (42,43). Ectopic expression of the bHLH TF Atoh1 (also known as Math1) results in conversion of nonsensory cochlear cells into functional sensory hair cells (44,45).…”

“…Ectopic expression of the bHLH TF Atoh1 (also known as Math1) results in conversion of nonsensory cochlear cells into functional sensory hair cells (44,45). Conversely, expression of Prox1 in sensory hair cells leads to the repression of Gfi1 and Atoh1, factors required for sensory hair cell specification, resulting in cellular degeneration (43).…”