Reprogramming nuclei

A fundamental question in cell and developmental biology concerns how nuclei progressively acquire differentiated functions. Although the nucleus of a fertilized egg is totipotent in that all of the differentiated cell types found in the adult organism can be derived from it, this is not the case for the vast majority of somatic nuclei in the adult animal. This limitation of the genomic potential of nuclei is progressively acquired during embryonic and post-embryonic development. Although in most cells the DNA sequence content of nuclei remains unchanged as development proceeds, the repertoire of genes that are expressed in a given cell type becomes limited. It also becomes more difficult to reactivate genes that are silenced in that cell type. This limitation is now known to reflect the imposition of epigenetic regulatory mechanisms on genes, especially through the assembly of stable repressive nucleoprotein complexes in the differentiated cell nucleus. The molecular mechanisms necessary to stably repress genes are gradually established as embryogenesis and post-embryonic development proceed. Remarkably, the egg and oocyte can reverse this process of repression, disassembling repressive features of nuclear organization and, in particular circumstances, recreating a state of pluripotency and even totipotency. The economic and medical implications of widespread cloning of domestic animals by nuclear transfer from donor embryos (Campbell et al., 1996; First and Pvather, 1991; Wolf et al., 1998), together with the potential for successful cloning of mammals using adult cell nuclei as donors (Wilmut et al., 1997; Wakayama et al., 1998; Kato et al., 1998; Wakayama and Yanagimachi, 1999), have stimulated interest in the basic molecular mechanisms involved in reprogramming the developmental fate of nuclei introduced into eggs and oocytes considerably. An understanding of these mechanisms not only will potentially provide insight into the significance of epigenetic events in establishing a developmental and differentiative program, but also might suggest new approaches towards improving the efficiency and success of nuclear transfer procedures.