A transient wave of BMP signaling in the retina is necessary for Müller glial differentiation

Development. 2015 Feb 1;142(3):533-43. doi: 10.1242/dev.118745.

Abstract

The primary glial cells in the retina, the Müller 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 Müller glial differentiation. In the course of our analysis of the BMP signaling pathway, we observed a transient 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 Müller glia-specific genes Rlbp1 and Glul, and the failure of many of the Müller glia to repress the bipolar/photoreceptor gene Otx2. These changes in normal Müller 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 Müller 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.

Keywords: Glia; Id1; Mouse; Neurogenesis; Smad.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Blotting, Western
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation / physiology*
  • Chromatin Immunoprecipitation
  • DNA Primers / genetics
  • Ependymoglial Cells / physiology*
  • Gene Knock-In Techniques
  • Immunohistochemistry
  • In Situ Hybridization
  • Mice
  • Mice, Inbred C57BL
  • Neurogenesis / physiology*
  • Real-Time Polymerase Chain Reaction
  • Retina / growth & development*
  • Signal Transduction / physiology*

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Proteins
  • DNA Primers