The majority of cloned animals derived by nuclear transfer from somatic cell nuclei develop to the blastocyst stage

After historic experiments by Briggs and King (Briggs and King, 1957; Briggs and King, 1952), animal cloning has emerged as a key approach to explore functional changes in the nuclear genome during differentiation (Gurdon, 1974; Gurdon, 1999; Kikyo and Wolffe, 2000; Rideout et al., 2001; Solter, 2000). Studies in amphibians have revealed that the potential of the nucleus to direct normal embryonic development decreases progressively with the developmental stage of the donor cell (Briggs and King, 1960; Gurdon, 1962; Gurdon et al., 1975). Similarly, in mammals, a direct relationship has been observed between the state of differentiation of a donor nucleus and its ability to generate cloned animals upon transfer into the oocyte (Campbell et al., 1996; Solter, 2000; Tsunoda et al., 1987; Willadsen, 1986). This was established most clearly in mouse cloning experiments using donor nuclei from somatic and pluripotent embryonic stem (ES) cells (Eggan et al., 2001; Rideout et al., 2000). Somatic and ES cell clones that develop to the blastocyst stage in vitro develop very differently in utero after their transfer to recipient animals. As in all other mammals where nuclear cloning has been successful, only a small fraction (1-3%) of mouse blastocysts derived from somatic donor nuclei develop to term, and even fewer reach adulthood (Wakayama et al., 1998; Wakayama and Yanagimachi, 1999; Wakayama and Yanagimachi, 2001). By contrast, up to a third of blastocysts from mouse clones made by nuclear transfer of ES cell donor nuclei develop to birth (Eggan et al., 2001; Rideout et al., 2000). These observations reinforce the notion that a progressive decrease or loss of nuclear potency during cell differentiation is a general characteristic of vertebrate development. Although as many as 70% of somatic clones can develop to the blastocyst stage in vitro after nuclear transfer, most arrest soon after implantation (Wakayama and Yanagimachi, 1999). Homozygous mutant embryos lacking Oct4 (Pou5f1 – Mouse Genome Informatics), a gene that encodes a POU-domain transcription factor that has an essential role in the control of developmental pluripotency, form morphologically normal but developmentally deficient blastocysts (Nichols et al., 1998; 1673 Development 130, 1673-1680 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00366