The first cloned mammals from somatic cell nuclei were sheep generated by a cell fusion method (Wilmut et al, 1997).  Subsequently, a microinjection method was developed to clone mice by selective nuclear transfer (Wakayama et al., 1998).  Species cloned by these methods include cow (Kato, et al., 1998; Cibelli et al., 1998; Wells, et al., 1999), goat (Baguisi, et al., 1999), pig (Onishi et al., 2000; Polejaeva et al., 2000), cat (Shin et al., 2002), rabbit (Chesne et al., 2002), house (Galli et al., 2003) mule (Woods et al., 2003), rat (Zhou et al., 2003) and dog (Lee et al., 2005).  The range of cloning efficiencies is 0 to ~20%, but a rate of ~1-2% (ie one or two live offspring per hundred embryos that started developing) is typical.  Although most cloning studies have used farm animals, these species are expensive and highly out-bred (genetically heterogeneous) relative to strains of laboratory mice.  By contrast, the short generation period (~2 months, including a gestation period of 19.5 days), low cost and small size of the mouse, coupled to a relatively good understanding of mouse gamete biology, embryology, development, husbandry and genetics today make it the archetypal mammalian model species.

No historical account of cloning is complete without reference to the first report of cloned mice (Illmensee and Hoppe, 1981).  The paper described production of three mice (one male and two females) by the co-ordinated microinjection of inner cell mass (ICM) cell nuclei into zygotes and immediate removal of the pre-existing pronuclei.  However, the report triggered controversy and disbelief as other investigators failed to repeat or corroborate the method (McGrath and Solter, 1983, 1984a).  By the end of the 1980s, only the nuclei of 1- or 2-cell embryos were shown to program full mouse development following transfer into an enucleated zygote or 2-cell embryo blastomere (McGrath and Solter, 1983, 1984a; Tsunoda, et al., 1987; Howlett et al., 1987).

The earliest generally accepted report of cloned mouse offspring (Tsunoda, et al., 1987) described an approach postulated earlier for cattle (Robl, et al., 1986).  In this method, 2-cell (not 1-cell) embryos provided recipient cytoplasm, with blastomeres from 8-cell embryos furnishing donor nuclei.  Yet reports of mouse cloning in the late 1980s and early 1990s were sparse with no success using nuclei from differentiated cells, suggesting that the approaches being taken were flawed.  Moreover, the first cloned mammals (sheep) had been produced by transferring donor nuclei into recipient, unfertilized eggs (oocytes), not 1- or 2-cell embryos (Willadsen, et al., 1986).  These factors may have contributed to the change to using oocytes as recipient cells in mouse nt (Kono, et al., 1991; Cheong, et al., 1993).  However, notwithstanding the relative ease of mouse embryo culture and manipulation, mouse metaphase-II oocytes (in contrast to those of most other species) are so sensitive that conventional microinjection through pipettes wider than 2 ?m at their tips is impracticable, resulting in lysis.  The intractability of microinjecting mouse metaphase II (MII) oocytes was eventually overcome with the application of piezo-actuated micromanipulation (Kimura and Yanagimachi, 1995).  This permitted the use of larger microinjection needles, although the realization that they could be utilized in nuclear transfer to clone mice came later (Wakayama et al., 1998a).

Whilst mouse cloning remained at an impasse, progress in large animal cloning accelerated rapidly and in the first half of the 1990s larger animals became the models of choice for nuclear transfer (Sun and Moor, 1995).  Success in larger animals was endorsed by the view that the zygotic switch occurred relatively late in these species, but at the early 2-cell stage in the mouse (Flach et al., 1982; Latham et al., 1991; Ram and Schultz 1993).  Early onset of zygotic genome activation - such as that believed to occur in the mouse - would imply less time for a newly-transferred nuclear genome to undergo the reprogramming (defined below) mandatory for development.  Mice were cloned following fusion of enucleated oocytes to the blastomeres of late 2-cell embryos (Kono et al., 1991), and later those of early 8-cell embryos (Cheong et al., 1993), yet these isolated successes had been equaled or surpassed in the first report of sheep cloning (Willadsen, 1986).  Not until later was it possible to clone mice by the serial transfer of nuclei from morula- or blastocyst- (ICM-) derived cell nuclei first into enucleated oocytes and then the blastomeres of 2-cell embryos (Tsunoda and Kato 1997, 1998).  Such serial transfer marks a key departure from the earlier method of Hoppe and Illmensee (1981) and may have facilitated reprogramming of the donor cell nuclei.

Cloning by transfer of somatic cell nuclei from adult mice was finally achieved using a single transfer step in 1997 (Wakayama et al., 1998a), marking the beginning of a new chapter in mouse cloning.  In this development, mouse nuclear transfer biology was brought alongside that of the larger species (Wilmut et al., 1997; Kato et al., 1998; Wakayama et al., 1998). The birth of Dolly the sheep following a fusion-based cloning method had been reported in 1997; the first surviving cloned mouse, Cumulina, was also born in that year, on October 3^rd and took her name from the cumulus cell nucleus from which she was derived.