pluripotency

One of the main focuses of the Merrill lab is to understand the underlying molecular control of pluripotency and cell fate decisions. Pluripotency can be defined as the ability to contribute cellular material to all cell lineages present in the adult. This differs from totipotency, which can be defined as the ability to all cell lineages in the adult and the embryo including extra-embryonic lineages in the placent and yolk sac. The fertilized egg (zygote) is an example of a totipotent cell.

Several different cell types have displayed properties of pluripotency. The most well known are mouse embryonic stem cells (ESC). ESC are derived from the inner cell mass (ICM) of the blastocyst, and can proliferate indefinately in tissue culture. If given the right mix of factor in vitro, ESC will maintain the property of pluripotency indefinately. The process of maintaining plruipotency while proliferating is frequently called self-renewal. The figure on the right shows an ES cell with the cell fate decisions that it can make. The curved arrow pointing back onto itself reflects its potential for self renewal. The arrows pointed to mesoderm, endoderm, and ectoderm reflect its potential to differentiate towards all different cell lineages.

In addition to ESC, several other cell types have been shown to display pluripotency. Examples of pluripotent cells include embryonic germ cells derived from primordial germ cells, epiblast cells from the post-implantation stage embryo (see gastrulation page), and induced pluripotent cells (iPS) derived from fibroblasts (Takahashi and Yamanaka, Cell, 2006). The mechanisms by which each of these cell types are able to be pluripotent remain relatively poorly understood. The fact that there are several different types of cells that display pluripotency suggests two possibilities: 1) They each share a common molecular mechanism enabling pluripotency, or 2) Several different molecular mechanisms may be capable of enabling pluripotency in vitro.

In the Merrill lab, we address the problem of identifying the mechanisms promoting pluripotency by examining how pluripotency is controlled in cells in their normal envioronment, in the embryo. We discover molecular relationships between gene products with appropriate in vitro systems such as ESC, and test whether these
molecular relationships are relevant for normal control of pluripotency in vivo. The first
molecular relationship that we have found is one between Tcf3-mediated repression
and the transcription factor Nanog. Nanog has been described as being part of a
feedforward system of transcription regulation together with Oct4 and Sox2 transcription
factors. This feedforward relationship is thought provide a robust mechanism to support
plruipotency in ESC and in the ICM of blastocysts. Experiments that will determined
if Tcf3-mediated repression of Nanog transcription plays a role in regulating pluripotency

in the intact embryo.