Design principles of pluripotency

Pluripotency is the capacity of individual cells to initiate all lineages of the mature organism in a flexible manner directed by signals in the embryo or cell culture environment. It is the keystone of mammalian development and of embryonic stem cell (ES) biology. A pluripotent cell has no predetermined programme; it is a blank slate. » A pluripotent cell has no predetermined programme; it is a blank slate. « What are the design principles of this unrestricted cell state? Genetic and cell biological studies point to transcription factor command rather than epigenetic governance (Niwa, 2007; Silva & Smith, 2008). Persuasive support for this view comes from the remarkable discovery of Shinya Yamanaka that pluripotency can be recreated from somatic cells through transcription factor induced reprogramming (Takahashi & Yamanaka, 2006). So how is this unique status acquired, how can it be maintained, and how is the exit path(s) to committed lineage progenitors routed? These are some of the questions that my laboratory is addressing. What follows here is a personal perception of the underlying design principles of pluripotency and lineage determination.Mammalian embryos develop from a small group of 10–20 pluripotent cells that form a few days after fertilization. The pluripotent state is established under the direction of two transcriptional organizers, Oct4 and (Niwa, 2007). It is no coincidence that both of these factors were originally identified based on their expression in pluripotent cells and germ cells, and absence from somatic cells. Without either factor, cells destined to become pluripotent in the blastocyst never acquire the ability to generate embryonic lineages (Mitsui et al, 2003; Nichols et al, 1998; Silva et al, 2009).Oct4 also drives the developmental progression towards lineage commitment by inducing expression of fibroblast growth factor 4 (Fgf4). This factor acts back on pluripotent …