EGF stimulates muller glial proliferation via a BMP-dependent mechanism

Muller glia, the major type of glia in the retina, are mitotically quiescent under normal conditions, though they can be stimulated to proliferate in some pathological states. Among these stimuli, EGF is known to be a potent mitogen for Muller glia. However, the signaling pathways required for EGF-mediated proliferation of Muller glia are not clearly understood. In this study, postnatal day 12 (P12) or adult trp53/ mouse retinas were explanted and cultured in the presence of EGF to stimulate Muller glial proliferation. Treatment with signaling inhibitors showed that activation of both MEK/ERK1/2 and PI3K/AKT pathways is required for EGF-induced proliferation of Muller glia. Interestingly, BMP/Smad1/5/8 activation downstream of PI3K/AKT signaling was also necessary for robust Muller glial proliferation, though activation of BMP/Smad1/5/8 signaling alone failed to stimulate their proliferation. In dissociated Muller glial culture, treatment with EGF induced the upregulation of Bmp7, and this upregulation was blocked significantly by co-treatment with the BMP inhibitor dorsomorphin, suggesting that BMP/Smad1/5/8 activation is mediated at least in part by an autocrine mechanism in Muller glia. A better understanding of how BMP/Smad1/5/8 signaling is involved in glial proliferation may have important implications for proliferative disorders, as well as for retinal regeneration in mammalian retinas.