Department of Molecular and Cellular Biology, Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center
Ronin and caspases in embryonic stem cells:
A new perspective on regulation of the pluripotent stage
Dr. Zwaka received the award for his research on the regulation of pluripotency in embryonic stem (ES) cells. His work focuses on caspases and their role in early differentiation events in ES cells and embryos. Caspases are well known to play a key role in programmed cell death, but Dr. Zwaka observed that particular caspases peaked in expression precisely when ES cells were differentiating, and that the cells that expressed these high levels did not die, but were simply differentiated. He also found that one of the classic players of ES cell self-renewal, NANOG, may be a target of caspase - thus, its cleavage by caspases would inactivate its self-renewal functions, and thereby trigger differentiation.
Through a yeast-two-hybrid screen designed to identify additional proteins cleaved by caspases during ES cell differentiation, Dr. Zwaka identified an unstudied protein he named Ronin (previously called Thap11). In a series of experiments, the Zwaka laboratory showed that Ronin is an important regulator of ES pluripotency that works at least partly independently of the classical pluripotency factors such as Oct4 and Nanog. These studies demonstrated that even in the absence of Oct4, Ronin can maintain a pluripotent state of ES cells. The discovery of an independent pathway for pluripotency raises the possibility that Ronin, alone or in combination with other factors, may be able to be used to induce pluripotentiality in non-stem cells. The discovery of Ronin gives specific insight into mechanisms of pluripotency, but also has long-term implications for strategies to generate stem cell-like cells.
Dr. Zwaka's nomination was based on the following publications:
Fujita J, Crane AM, Souza MK, Dejosez M, Kyba M, Flavell RA, Thomson JA, Zwaka TP.Caspase Activity Mediates the Differentiation of Embryonic Stem Cells. 2008 Jun 5;2(6):595-601.
Dejosez M, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, Songyang Z, Thomson JA, Zwaka TP. Ronin Is Essential for Embryogenesis and the Pluripotency of Mouse Embryonic Stem Cells. Cell 2008 Jun 27;133(7):1162-74.