Radial glia cells in the central nervous system serve as an important source of progenitor cells for generating a range of neural cell types. Retinal regeneration in vertebrates relies on a specialised type of radial glia, called Müller glia, which are normally quiescent but can be stimulated to undergo proliferation and differentiation in order to generate new neurons. In this issue (p. 1859 and p. 1874), two studies shed light on the molecular mechanisms that regulate Müller glia activation and proliferation in response to injury and in different vertebrate species.
In the first study, Andy Fischer and colleagues investigate the role of mTor signalling in the formation of Müller glia-derived progenitor cells (MGPCs) in the chick retina. The authors use NMDA to induce a cytotoxic response, and observe that mTor signalling is transiently activated upon activation of Müller glia cells. Inhibition of mTor signalling in vivo prevents the proliferation of the Müller glia cells and blocks the regenerative response. Using a range of inhibitors and readouts, the authors show that mTor signalling is required for the proliferation of MGPCs. The authors further show that mTor signalling is activated in response to insulin, IGF1 and FGF2, and that this response is most likely independent of the MAPK pathway.
In the second study, Joachim Wittbrodt and colleagues look at the role of a single factor, Atoh7, in directing Müller glia cells to proliferate and differentiate in the absence of an injury. The authors use a fluorescent transcriptional reporter of atoh7 to demonstrate atoh7 expression in proliferating Müller glia cells after retinal injury in medaka. The authors then use an inducible system to activate expression of atoh7 in vivo in the Müller glia cells, and find that this is sufficient to drive the cells to re-enter the cell cycle and undergo proliferation. Forced expression of atoh7 in these cells activates Notch signalling, and indeed the authors show that overexpression of the Notch intracellular domain can recapitulate the effects seen by atoh7 overexpression. Importantly, not only did atoh7 overexpression in Müller glia lead to cell cycle re-entry and proliferation, but the authors also observed the formation of neurogenic clusters and subsequent de novo neurogenesis following atoh7 overexpression in these cells. Together, these two studies bring together novel and exciting findings regarding the regulation of Müller glia proliferation following injury and the subsequent regenerative response.