A transient wave of bmp signaling in the retina is necessary for muller glial differentiation

Abstract

The primary glial cells in the retina, the Muller glia, differentiate from retinal progenitors in the first postnatal week. CNTF/LIF/STAT3 signaling has been shown to promote their differentiation; however, another key glial differentiation signal, BMP, has not been examined during this period of Muller glial differentiation. In the course of our analysis of the BMP signaling pathway, we observed atransient wave of Smad1/5/8 signaling in the inner nuclear layer at the end of the first postnatal week, from postnatal day (P) 5 to P9, after the end of neurogenesis. To determine the function of this transient wave, we blocked BMP signaling during this period in vitro or in vivo, using either a BMP receptor antagonist or noggin (Nog). Either treatment leads to a reduction in expression of the Muller glia-specific genes Rlbp1 and Glul, and the failure of many of the Muller glia to repress the bipolar/photoreceptor gene Otx2. These changes in normal Muller glial differentiation result in permanent disruption of the retina, including defects in the outer limiting membrane, rosette formation and a reduction in functional acuity. Our results thus show that Muller glia require a transient BMP signal at the end of neurogenesis to fully repress the neural gene expression program and to promote glial gene expression.