SMAD7 deficiency stimulates Müller progenitor cell proliferation during the development of the mammalian retina.

The transforming growth factor-ß (TGF-ß) pathway contributes to maintain the quiescence of adult neural stem and progenitor cells in the brain. In the retina, Müller cells are discussed to represent a glial cell population with progenitor-like characteristics. Here, we aimed to investigate if elevated TGF-ß signaling modulates the proliferation of Müller cells during retinal development. We generated mutant mice with a systemic, heterozygous up-regulation of TGF-ß signaling by deleting its inhibitor SMAD7. We investigated apoptosis, proliferation, and differentiation of Müller cells in the developing retina. We show that a heterozygous deletion of SMAD7 results in an increased proliferation of Müller cell progenitors in the central retina at postnatal day 4, the time window when Müller cells differentiate in the mouse retina. This in turn results in a thickened retina and inner nuclear layer and a higher number of differentiated Müller cells in the more developed retina. Müller cells in mutant mice contain higher amounts of nestin than those of control animals which indicates that the increase in TGF-ß signaling activity during retinal development contribute to maintain some progenitor-like characteristics in Müller cells even after their differentiation period. We conclude that TGF-ß signaling influences Müller cell proliferation and differentiation during retinal development.

Heterozygous modulation of TGF-ß signaling does not influence Müller glia cell reactivity or proliferation following NMDA-induced damage.

The stimulation of progenitor or stem cells proliferation in the retina could be a therapeutic avenue for the treatment of various ocular neurodegenerative disorders. Müller glia cells have been discussed to represent a progenitor cell population in the adult retina. In the brain, TGF-ß signaling regulates the fate of stem cells; however, its role in the vertebrate retina is unclear. We therefore investigated whether manipulation of the TGF-ß signaling pathway is sufficient to promote Müller glia cell proliferation and subsequently their trans-differentiation into retinal neurons. To this end, we used mice with heterozygous deficiency of the essential TGF-ß receptor type II or of the inhibitory protein SMAD7, in order to down- or up-regulate the activity of TGF-ß signaling, respectively. Excitotoxic damage was applied by intravitreal N-methyl-D-aspartate injection, and BrdU pulse experiments were used to label proliferative cells. Although we successfully stimulated Müller glia cell reactivity, our findings indicate that a moderate modulation of TGF-ß signaling is not sufficient to provoke Müller glia cell proliferation. Hence, TGF-ß signaling in the retina might not be the essential causative factor to maintain mammalian Müller cells in a quiescent, non-proliferative state that prevents a stem cell-like function.