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Yumi Ueki, Kristin Cox, Thomas Reh; BMP-Smad1/5/8 Signaling is Necessary for Development of Müller Glia. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3748.
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© ARVO (1962-2015); The Authors (2016-present)
It is known that BMP signaling promotes astroglial differentiation in cortex, but the role of BMP signaling in Müller glial development in the retina has not been studied. The purpose of this study was to investigate the role of BMP-Smad1/5/8 signaling in Müller glial development.
All experiments involving animals were performed according to the ARVO statement for the Use of Animals in Ophthalmic and Vision Research. C57BL/6 mouse retinas were collected at various ages between postnatal day 0 (P0) and P21, and the expression and activation of Smad1/5/8 were analyzed by immunohistochemistry (IHC), real-time qPCR, and Western blot (WB). Retinas were explanted at P3 or P6 and treated with BMP4 or a BMP inhibitor dorsomorphin (DM) for 5 days in order to activate or inhibit Smad1/5/8, respectively. The expression of Müller glial markers, including cellular retinaldehyde-binding protein (CRALBP), glutamine synthatase (GS), and Sox9 was analyzed by IHC and WB. Intravitreal injection of DM was performed at P5 to inhibit BMP-Smad1/5/8 signaling in vivo, and retinas were collected at P6 for analysis of glial marker expression. Expression of inhibitor of differentiation 1 (Id1), a known target of BMP-Smad1/5/8 signaling, was analyzed between P0-P21 by IHC, qPCR, and WB.
Smad1/5/8 was transiently but robustly activated in the inner nuclear layer, including developing Müller glia between P5-P8. When P3 or P6 retinal explants were treated with DM for 5 days in vitro, there was a significant reduction in Müller glial markers (CRALBP, GS, Sox9, and Sox2). Smad1/5/8 activation and CRALBP expression were also significantly attenuated with the treatment of P5 retinas with DM for 1 day in vivo. Starting around P6, Müller glia express Id1 in a BMP-dependent manner.
Our data suggest that activation of BMP-Smad1/5/8 signaling is necessary for the development of Müller glia. Id1 may be one of the downstream effectors that regulate glial gene expression.
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