Abstract
Here we present spatio-temporal localization of Kremen1, a transmembrane receptor, in the mammalian cochlea, and investigate its role in the formation of sensory organs in mammal and fish model organisms. We show that Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Based on this expression pattern, we investigated whether Kremen1 functions to modulate cell fate decisions in the prosensory domain of the developing cochlea. We used gain and loss-of-function experiments to show that Kremen1 is sufficient to bias cells towards supporting cell fate, and is implicated in suppression of hair cell formation. In addition to our findings in the mouse cochlea, we examined the effects of over expression and loss of Kremen1 in the zebrafish lateral line. In agreement with our mouse data, we show that over expression of Kremen1 has a negative effect on the number of mechanosensory cells that form in the zebrafish neuromasts, and that fish lacking Kremen1 protein develop more hair cells per neuromast compared to wild type fish. Collectively, these data support an inhibitory role for Kremen1 in hair cell fate specification.
Highlights
Kremen[1] is a single pass transmembrane protein that acts as a receptor to members of the dickkopf (Dkk) family of Wnt antagonists[7]
Based on previous reports that place Kremen[1] atop the Wnt cascade acting to inhibit Wnt binding to its cogent receptors, we examined the effects of manipulating receptor composition on Wnt responsive cells of the cochlea
Through gain and loss-of-function experiments, we show that Kremen[1] is involved in regulation of cell fate decisions in the mammalian cochlea and the zebrafish lateral line
Summary
Kremen[1] is a single pass transmembrane protein that acts as a receptor to members of the dickkopf (Dkk) family of Wnt antagonists[7]. Kremen[1] functions as part of a Wnt inhibitory complex that prevents Lrp5/6 mediated sequestration of Gsk3β7, allowing it to target cytoplasmic β-catenin for degradation. On receipt of a Dkk ligand Kremen[1] associates with Lrp5/6, removing it from the cell surface via clathrin mediated endocytosis, attenuating Wnt signal transduction[7,8,9]. Based on previous reports that place Kremen[1] atop the Wnt cascade acting to inhibit Wnt binding to its cogent receptors, we examined the effects of manipulating receptor composition on Wnt responsive cells of the cochlea. Through gain and loss-of-function experiments, we show that Kremen[1] is involved in regulation of cell fate decisions in the mammalian cochlea and the zebrafish lateral line
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