T.P. Zwaka

Organiser's Note: This talk was cancelled by the presenter, and therefore no video is available.

Embryonic stem (ES) and ES-like cells afford ideal model systems for unraveling the complex molecular networks that give rise to cellular identity. They are relatively easy to generate and maintain in culture and are amenable to manipulation with the growing repertoire of molecular research tools now in the hands of cell biologists. More importantly, they have the property of pluripotency, meaning that they can differentiate to many cell types in the body, even to germ cells.

Several groups believe that a small core set of regulatory factors, including Pou5f1 (encoding the Oct4 protein), Sox2 and Nanog, maintain ES cells in the pluripotent state by acting on a limited number of target genes. This fundamental concept has generated enormous excitement in the biomedical community, leading to successful reprogramming of somatic cells to an ES-like state. Yet, recent discoveries in my laboratory suggest that the complement of factors needed to direct ES cell pluripotency maybe considerably larger than originally thought.

Starting with the premise that stem cell differentiation corresponds to a loss of self-renewal capacity, we recently showed that caspase-3- mediated cleavage of Nanog is a conserved inductive cue for stem cell differentiation. This progress was rapidly followed by a study in which I identified a previously unrecognized protein, Ronin, as a central player in the control of embryogenesis and ES cell differentiation, apparently through epigenetic silencing of large segments of the genome. Thus, the mechanisms that govern stem cell- fate decisions appear to extend far beyond the restricted regulatory circuit first envisioned for Oct4. Indeed, my observation on caspase-3 and Ronin raise a number of intriguing questions that have become the focus of continuing work in mammalian tissue development and maintenance.

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