Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Overview: Glial cells have an extraordinary ability to function either as differentiated support cells in the central nervous system, or as resident stem cells, undergoing de-differentiation and proliferation before giving rise to new neurons. Mobilization of glial cells to become stem cell-like is a natural response to eye growth, injury or disease in cold-blooded vertebrates (ectotherms), such as fish and frogs. In contrast, glial mobilization is much more limited in warm-blooded vertebrates (endotherms), including mammals. We study glial cell activation in the murine retina, where Muller glia (MG) are a potential source of stem cells. However, tissue regeneration via a MG self-healing repair mechanism does not occur readily in endotherms. Instead, the favored response of MG to injury in endotherms is reactive gliosis, a neuroprotective response that can have accompanying cytotoxic effects.

To decipher how mammalian MG make the choice to either remain as differentiated support cells, re-enter the cell cycle as stem cells, or undergo reactive gliosis, we focus on the zinc finger transcription factor Zac1 . We found that MG undergo injury-independent gliosis in Zac1 null mutant mice. Zac1 is a maternally imprinted gene and part of an imprinted gene network (IGN) of co-regulated genes. We thus hypothesize that Zac1 maintains MG in a quiescent, differentiated state, acting via the IGN to prevent reactive gliosis and possibly stem cell-repair. To test this hypothesis we will:

Aim 1. Assess the normal role of Zac1 in maintaining a differentiated MG phenotype. We assess Zac1 function in maintaining a differentiated MG fate in the uninjured eye by characterizing the fate of Zac1 mutant MG and by assessing their responsiveness to non-injury inductive cues.
Aim 2. Examine the role of Zac1 in the MG injury response. To determine whether Zac1 participates in injury-dependent MG responses, we assess Zac1 expression in response to various stressors, and ask whether Zac1 overexpression is protective in MG.
Aim 3. Determine whether Zac1 acts through the IGN to maintain a mature MG phenotype. To test whether Zac1 acts through the IGN to maintain MG in a differentiated state, we study the expression of IGN genes in Zac1 mutant MG and injury models, and perform IGN functional tests with loss- and gain-of-function studies.

Impact: This project will enhance our fundamental knowledge of MG biology, with applications to the general field of stem cell biology and tissue regeneration. HQP will be exposed to innovative, state-of-the-art techniques that will allow them to be competitive in today's knowledge-based economy.