Role of TGF-β activated kinase 1 (TAK1) in chick retinal development
Abstract
Cell cycle exit and concomitant commitment to a differentiated cell fate are critical processes that require an intricate communication between intrinsic guides within the cell and extrinsic cues from the environment. As the focal points of various signaling pathways, the mitogen activated protein kinases (MAPK) are the crossroads at which a multitude of extrinsic signals converge and are relayed to the cell. TGF-β activated kinase 1 (TAK1), a MAP3K known to be activated downstream of BMP and TGF-β signaling, is increasingly being implicated in control of proliferation and differentiation in many cell types. Clues to its mechanism come from in vitro studies that have shown TAK1 to inhibit a G1-S phase cyclin D1, a protein critical to progression of cell cycle. As such, TAK1 has the potential to act as an intermediary that translates extrinsic cues to intrinsic cell fate decisions in the retina. Using the embryonic chick as a model for vertebrate retinal development, we have performed immunohistochemistry using an antibody that specifically detects the activated form of TAK1 (pTAK1). This has revealed, for the first time, the extensive localization of pTAK1 in a subset of differentiated cells and more prominently, in the mitotic progenitor cells of the retina. Our preliminary studies aimed at in vivo pharmacological inhibition of TAK1 activity, using (5Z)-7-Oxozeaenol, in the developing chick eye, show that TAK1 inhibition down-regulates the JNK MAPK pathway while resulting in an increase in progenitor cell population, paralleled by a decrease in differentiated cell types. The nuclear localization of both active and inactive TAK1 is a novel finding of this study that contrasts the known cytoplasmic localization and might suggest unique roles for TAK1 in retinal cells. This is the first study to show that TAK1 signaling is active during retinal development and potentially regulates exit of retinal progenitors from the cell cycle.
Degree
M.S.
Advisors
Adams, Purdue University.
Subject Area
Biology|Cellular biology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.