Located in discrete regions of the adult mammalian CNS, neural stems cells are specialized types of glia. M?ller glia are the principal glial cell of he vertebrate retina and represent a dormant progenitor cell population in the adult CNS. These cells maintain retinal architecture, provide trophic support for neurons, and modulate neuronal activity, thus sustaining retinal homeostasis. M?ller glia, however, do not irreversibly leave the progenitor state - they can re-enter the mitotic cycle to generate new neurons, and are therefore considered the key target cell for retinal regenerative studies. Unlike in other regions of the adut CNS, no documented cases of M?ller glial cell transformation have been reported (Jadhav, 2009). These observations suggest the existence of tightly regulated molecular mechanisms that protect the retina from uncontrolled proliferation of M?ller glial cells. We, and others, have previously shown that SOX2 is a core transcriptional regulator of pluripotentiality of embryonic stem cells (Avilion et al., 2003). In the developing and adult CNS, expression of SOX2 defines multipotent neural progenitor cells capable of giving rise to both neurons and glia. Several studies conducted in a variety of experimental systems demonstrated that, consistent with its expression pattern, SOX2 controls maintenance of neural progenitor cell identity;disruption of SOX2 function is associated with the loss of proliferative and differentiation capacity in neural progenitor cells, accompanied by the loss of their radial morphology (Favaro et al., 2009;Ferri et al., 2004;Pevny and Nicolis, 2010). Specifically, perturbation of SOX2 function by expression of dominant- interfering versions of SOX2 results in premature terminal differentiation of chick spinal cord progenitors (Bylund et al., 2003;Graham et al., 2003;Holmberg et al., 2008). Moreover, we have recently demonstrated that genetic ablation of SOX2 in the optic cup results in complete loss of retinal neuronal competence (Taranova et al 2006;Matsushima et al., 2011). However, it remains unknown what is the precise cellular mechanism regulated by SOX2 in the maintenance of adult progenitor identity. In this study, we will utilize mouse genetics combined with real-time imaging approaches to establish the role of SOX2 in the specification and function of M?ller glial cells. Our preliminary data show that two key progenitor characteristics of M?ller glia, their pseudoepithelial morphology and cell cycle quiescence, are disrupted following conditional genetic ablation of Sox2, leading to M?ller cell depletion and retinal degeneration. Moreover, our studies have revealed that ablation of SOX2 in the postnatal retina results in aberrant cell division of M?ller glial cells. Collectively, this work has led to the hypothesis tha SOX2 maintains M?ller glial cell homeostasis by preventing their depletion through cell division. The determination of the role of the SOX2 signaling pathway in healthy and diseased retina is required to fully understand regulation of both the quiescent state and the regenerative potential of retinal M?ller glia.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022341-03
Application #
8655886
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Greenwell, Thomas
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$315,931
Indirect Cost
$95,431
Name
University of North Carolina Chapel Hill
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Surzenko, Natalia; Crowl, Tessa; Bachleda, Amelia et al. (2013) SOX2 maintains the quiescent progenitor cell state of postnatal retinal Muller glia. Development 140:1445-56