TGF-  Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye

Abstract

We investigated the influence of transforming growth factor-␤ (TGF-␤) signaling on developmental programmed cell death in the mouse retina by direct and specific molecular targeting of TGF-␤ type II receptor (T␤RII) and Smad7 in retinal progenitor cells. Mice were generated carrying a conditional deletion of the T␤RII in cells that originate from the inner layer of the optic cup. The animals showed a significant decrease of phosphorylated Smad3 in both the central and peripheral retina, which indicates the diminished activity of TGF-␤ signaling. T␤RII deficiency significantly increased the apoptotic death of retinal neurons during embryonic and postnatal development without affecting their proliferation. In contrast, treatment with TGF-␤2 inhibited cell death of retinal ganglion cells in dissociated retinal cell cultures, an effect that was blocked by inhibiting the phosphorylation of Smad3. The increase in apoptosis during development resulted in a significant reduction in the number of neurons in adult T␤RII-deficient mice. The effect was most pronounced in the inner retina neurons and resulted in functional deficits as determined by electroretinography. In contrast, a conditional deletion of TGF-␤-inhibiting Smad7 in retinal neurons significantly enhanced Smad3 phosphorylation and significantly decreased apoptosis of retinal neurons in embryos and pups. Moreover, the number of retinal ganglion cells was significantly higher in Smad7-deficient mice compared with control littermates. T␤RII-deficient pups showed a lower level of nerve growth factor (NGF) in its mRNA; however, higher levels were observed in Smad7-deficient pups, which strongly suggests that the protective effects of TGF-␤ signaling on developmental cell death are mediated through NGF.

TGF-β is a potent inducer of Nerve Growth Factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain?

“…In line with that, Braunger et al showed in retinal progenitor cells of TGF-b1 receptor II deficient mice, Smad3 phosphorylation was decreased, which led to lower levels of NGF mRNA. Similarly, mice deficient in Smad7, which is a TGF-b1 signaling inhibitor, had higher Smad3 phosphorylation and higher levels of NGF mRNA 31 . In rat hippocampus, TGF-b1 increased NGF mRNA expression in vivo 32 .…”

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

“…Absence of the direct neurotrophic effects of VEGF (Kilic et al 2006;Nishijima et al 2007;SaintGeniez et al 2008;Robinson et al 2001;Cvetanovic et al 2011) may easily contribute to the changes in photoreceptor structure and function. Direct effects of the high TGF-β1 amounts on photoreceptor apoptosis are less likely, as we recently showed that TGF-β signaling rather protects developing retinal neurons from apoptotic death (Braunger et al 2013b). The lack of SMAD2/3 in the nuclei of βB1-TGF-β1 photoreceptors also argues against activation of the canonical TGF-β signaling cascade, a typical requirement for apoptosis driven by TGF-β.…”

Programmed Cell Death in Neurodevelopment

“…Developmental susceptibility to apoptosis is also regulated in Drosophila by microRNAs or epigenetic modification of chromatin (Hilgers et al, 2010;Zhang et al, 2008). In mammals, it is proposed that the susceptibility to neuronal apoptosis is controlled at the various levels: protection by growth factor signalings, the amount of IAP protein, redox regulation of cytochrome c, and downregulation of the apoptosome machinery and executioner caspases during differentiation and aging (Braunger et al, 2013;Donovan and Cotter, 2002;Donovan et al, 2006;Ohsawa et al, 2009;Stoka et al, 2006;Vaughn and Deshmukh, 2008;Wright et al, 2004Wright et al, , 2007. Thus, distinct mechanisms that account for differential susceptibility to apoptotic triggers exist in a differentiation state and cell-type-specific manner.…”