Deficiency in Retinal TGF beta Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways

Transforming growth factor beta (TGF beta) signaling has manifold functions such as regulation of cell growth, differentiation, migration, and apoptosis. Moreover, there is increasing evidence that it also acts in a neuroprotective manner. We recently showed that TGF beta receptor type 2 (Tgfbr2) is upregulated in retinal neurons and Muller cells during retinal degeneration. In this study we investigated if this upregulation of TGF beta signaling would have functional consequences in protecting retinal neurons. To this end, we analyzed the impact of TGF beta signaling on photoreceptor viability using mice with cell type-specific deletion of Tgfbr2 in retinal neurons and Muller cells (Tgfbr2(& UDelta;OC)) in combination with a genetic model of photoreceptor degeneration (VPP). We examined retinal morphology and the degree of photoreceptor degeneration, as well as alterations of the retinal transcriptome. In summary, retinal morphology was not altered due to TGF beta signaling deficiency. In contrast, VPP-induced photoreceptor degeneration was drastically exacerbated in double mutant mice (Tgfbr2(& UDelta;OC); VPP) by induction of pro-apoptotic genes and dysregulation of the MAP kinase pathway. Therefore, TGF beta signaling in retinal neurons and Muller cells exhibits a neuroprotective effect and might pose promising therapeutic options to attenuate photoreceptor degeneration in humans.