July 23, 2002

UCSD Researchers Identify Eye-Formation Strategy in Mice
That Provides Clues to Development of Other Organs

Researchers at the University of California, San Diego (UCSD) School of Medicine have discovered a linkage between proteins that is an essential part of the complex series of molecular events leading to normal eye development in mice. The investigators also suggest that the combination of specific proteins in eye formation may be similar to yet unidentified genes that act together to allow development of other organs.

Michael G. Rosenfeld, Ph.D.

Published in the July 19, 2002 issue of the journal Science, the research was done in the lab of Michael G. Rosenfeld, Ph.D., UCSD professor of medicine and an investigator with the Howard Hughes Medical Institute. The first author was Xue Li, Ph.D., a post-doctoral fellow in the Rosenfeld lab.

"A central issue in development of any mammalian organ is to get the right number of cells which make the size of each organ precise." Rosenfeld notes.

In studies with embryonic mice, the research team found that sine oculis/6 (Six6), one of a family of genes naturally expressed in eye development, actively enable normal eye size by stopping another set of genes that restrict eye cell-growth if left alone. Mice bred without the Six6 protein exhibited arrested eye development, sometimes with complete absence of optic nerve and optic chiasm, the location of x-crossed nerve fibers on the undersurface of the hypothalamus.

To determine if Six6 had a co-factor, or accomplice, in its developmental role, the researchers investigated it and other genes in cell cultures. They found that Six6 strongly interacted with another protein called dachshund/2 (Dach2). While Six6 alone exerted a weak repressive activity, it strongly assumed its normal role when associated with Dach2.

The research team also discovered that the linked Six6/Dach2 complex interacted with a gene called p27Kip1, a known inhibitor of cell proliferation. In cell cultures, they identified the region of the p27Kip1 gene where the Six6/Dach2 complex bound, then studied mouse retinas to prove that Six6/Dach2 regulated p27Kip1 acted together to control tissue growth.

The authors note in the paper that "together, these findings provide an organ-specific strategy for the expansion of precursor cell populations during development, a strategy likely to be used in other organ systems."

The Rosenfeld lab work was supported by grants from the National Institutes of Health, NRSA and Telethon/Italy.

In addition to Rosenfeld and Li, authors of the paper are Valentina Perissi, a UCSD graduate student, David W. Rose, Ph.D., UCSD associate professor of medicine, and Forrest Liu, M.D., UCSD Department of Medicine.

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