ERas, previously thought to be a pseudogene, was found by the group as being expressed specifically in ES cells. The other genes in this expression class are also expressed in early embryonic tissues such as the inner cell mass and epiblast, but no expression of ERas is evident in the embryo. The lack of phenotype of ERas knockout mice adds to the mystery.
Yamanaka suggests that ERas may be connected to the LIF/Stat3 pathway, which is dispensable for normal mouse development but necessary in ES cells and for the extended survival of mouse blastocysts (a process called diapause). Only in the ES cells and during diapause must pluripotency be extended past a few days, and this extension may be helped by LIF or ERas expression. The situation is clouded further in humans and monkeys, however, as both have apparently functional ERas genes but lack diapause.
Whatever the function of ERas, “ERas null cells should be much safer for clinical applications,” says Yamanaka. ERas has residues characteristic of activated Ras proteins, and is found largely in the activated, GTP-bound form. Its addition transforms cells, whereas its deletion from ES cells sharply reduces their tumor-forming ability. Growth is also reduced in ERas knockout cells, but Yamanaka says that rich culture conditions largely correct for this and thus slow growth should not hold back the use of altered ES cells. Direct human applications will not, however, come from Yamanaka's group in the foreseeable future, as there are extensive bureaucratic hurdles involved in experimentation on human ES cells in Japan. ▪