mTor signaling is required for the formation of proliferating Muller glia-derived progenitor cells in the chick retina

作者：Zelinka Christopher P; Volkov Leo; Goodman Zachary A; Todd Levi; Palazzo Isabella; Bishop William A; Fischer Andy J^*

来源：Development, 2016, 143(11): 1859-1873.

DOI：10.1242/dev.133215

• Muller glia
• mTor
• Progenitor
• Regeneration
• Retina

We investigate the roles of mTor signaling in the formation of Muller glia-derived progenitor cells (MGPCs) in the chick retina. During embryonic development, pS6 (a readout of active mTor signaling) is present in early-stage retinal progenitors, differentiating amacrine and ganglion cells, and late-stage progenitors or maturing Muller glia. By contrast, pS6 is present at low levels in a few scattered cell types in mature, healthy retina. Following retinal damage, in which MGPCs are known to form, mTor signaling is rapidly activated in Muller glia. Inhibition of mTor in damaged retinas prevented the accumulation of pS6 in Muller glia and reduced numbers of proliferating MGPCs. Inhibition of mTor had no effect on MAPK signaling or on upregulation of the stem cell factor Klf4, whereas Pax6 upregulation was significantly reduced. Inhibition of mTor potently blocked the MGPC-promoting effects of Hedgehog, Wnt and glucocorticoid signaling in damaged retinas. In the absence of retinal damage, insulin, IGF1 and FGF2 induced pS6 in Muller glia, and this was blocked by mTor inhibitor. In FGF2-treated retinas, in which MGPCs are known to form, inhibition of mTor blocked the accumulation of pS6, the upregulation of Pax6 and the formation of proliferating MGPCs. We conclude that mTor signaling is required, but not sufficient, to stimulate Muller glia to give rise to proliferating progenitors, and the network of signaling pathways that drive the formation of MGPCs requires activation of mTor.

• 出版日期2016-6-1