EGF stimulates Müller glial proliferation via a BMP-dependent mechanism.
Müller 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 Müller glia. However, the signaling pathways required for EGF-mediated proliferation of Müller 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 Müller 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 Müller glia. Interestingly, BMP/Smad1/5/8 activation downstream of PI3K/AKT signaling was also necessary for robust Müller glial proliferation, though activation of BMP/Smad1/5/8 signaling alone failed to stimulate their proliferation. In dissociated Müller 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 Müller 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.
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Yumi
Y
Ueki
Thomas A
TA
Reh
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D055419:Bone Morphogenetic Protein 7; D011720:Pyrazoles; D011743:Pyrimidines; C525820:bmp7 protein, mouse; C516138:dorsomorphin; D004815:Epidermal Growth Factor