Thomas Zwaka, M.D., Ph.D.
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. Caspase
Activity Mediates the Differentiation of Embryonic Stem Cells.
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.