EDWARD M. LEVINE
Ed Levine
email: ed.levine@utah.edu		 Associate Professor of Ophthalmology and Visual Sciences

Developmental Neuroscience
Molecular Neuroscience
Cellular Neuroscience

B.S. 1986, SUNY at Albany; Ph.D. 1994, SUNY at Stony Brook; Postdoctoral Fellow, 1995-1999, University of Washington, Seattle.

Image of an embryonic mouse eye at the beginning of retinal neurogenesis. The red boundary is the developing retinal pigmented epithelium. The red cells in the retina are newly specified neurons and cone photoreceptors and the turquoise cells are differentiating ganglion cells. The developing lens is the circular tissue in the "cup" of the eye.

RESEARCH:

Our laboratory has two primary areas of interest: to characterize the molecular and cellular mechanisms of eye development with an emphasis on the retina, and to identify the mechanisms that control the pathological activities of retinal glia that commonly occur during the course of retinal diseases and injuries. We study the mouse retina because its developmental progression is well understood, in vitro and in vivo approaches are well established, and powerful genetic models of retinal development and degeneration are available. Because of these advantages, we can identify and characterize important regulatory molecules and directly assay their functions.

Molecular and Cellular Mechanisms of Retinal Development
We are currently investigating how a group of homeodomain transcription factors act as master regulators to promote development of the retina from the earliest stages. We recently showed that the homedomain protein Lhx2 is essential for the patterning of the optic neuroepithelium through a combination of cell autonomous and non-autonomous mechanisms and without Lhx2, eyes never form. Another homeodomain protein, Vsx2, is also critical for retinal development. In contrast to Lhx2 mutants, eyes form in Vsx2 mutants, but they are severely reduced in size and the animals are blind. We have already determined that Chx10 is required for retinal progenitor cell proliferation and have identified cell cycle proteins and signaling pathways that require Vsx2 for their proper activity or expression. A major question relevant to these studies is whether Lhx2, Vsx2, and possibly other homeodomain proteins act to coordinate multiple pathways into molecular networks such that the processes of patterning, proliferation, and neurogenesis are executed in the proper manner. By addressing this important question, we will begin to understand the logic of the molecular circuitry that drives eye organogenesis.

Regulation of Glial Reactivity in Retinal Disease and Injury
In retinal diseases, the initial problem is typically confined to one cell type such as photoreceptors or retinal ganglion cells. However, other retinal cell types such as the retinal glia are also affected by becoming reactive, a stress response that has protective properties, but ultimately hastens the disease process. Similarly, in retinal injuries or detachment, glial reactivity often leads to scar formation, which hinders successful recovery and interferes with vision. We previously showed that p27Kip1, a cell cycle regulator that has both tumor suppressor and oncogenic activities, is also a negative regulator of glial reactivity. Presently, we are determining what aspect of p27Kip1 function is responsible for controlling reactivity with the ultimate goal of developing a treatment that can be used in the clinic.

Selected Publications

Yun, S., Saijoh, Y., Hirokawa, K.E., Kopinke, D., Murtaugh, L.C., Monuki, E.S., and Levine, E.M. (2009) Lhx2 links the intrinsic and extrinsic factors controlling optic cup formation. Development, in press.

Vazquez-Chona, F.R., Clark, A.M., and Levine, E.M. (2009) Rlbp1 promoter drives Muller cell-specific expression in transgenic mice. Investigative Ophthalmology and Visual Sciences, 50(8):3996-4003.

Das, G., Choi, Y., Sicinski, P., and Levine, E.M. (2009) Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells. BMC Neural Development, 4(1):15.

Sigulinsky, C., Green, E.S., Clark, A.M., and Levine, E.M. (2008) Vsx2/Chx10 ensures the correct timing and magnitude of Sonic Hedgehog signaling in retinal progenitor cells. Developmental Biology, 317:560-575.

Clark, A.M., Yun, S., Veien, E.S., Wu, Y.Y., Chow, R.L., Dorsky, R.I., and Levine, E.M. (2008) Negative regulation of Vsx1 by its paralog Chx10 is conserved in the vertebrate retina. Brain Research, 1192:99-113.

Dhomen, N.S., Balaggan, K.S., Bainbridge, J.W., Rae, J., Levine, E.M., Ali, R.R., and Sowden, J.C. (2006) Absence of Chx10 causes neural progenitors to persist in the adult retina. Investigative Ophthalmology and Visual Sciences, 47:386-396.

Levine, E.M., and Green, E.S. (2004) Cell-intrinsic regulators of proliferation in vertebrate retinal progenitors. Seminars in Cell and Developmental Biology, 15:63-74.

Green, E.S., Stubbs, J.L., and Levine, E.M. (2003) Genetic rescue of cell number in a mouse model of micropththalmia: interactions between Chx10 and G1 phase cell cycle regulators. Development, 130:539-552.

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