ANEMIA AND PERINATAL DEATH RESULT FROM LOSS OF THE MURINE ECOTROPIC RETROVIRUS RECEPTOR MCAT-1

The mCAT-1 gene encodes a basic amino acid transporter that also acts as the receptor for murine ecotropic leukemia viruses, Targeted mutage nesis in embryonic stem cells has been used to introduce a germ-line n ull mutation into this gene. This mutation removes a domain critical f or virus binding and inactivates amino acid transport activity. Homozy gous mutant pups generated from these cells were similar to 25% smalle r than normal littermates, very anemic, and died on the day of birth. Peripheral blood from homozygotes contained 50% fewer red blood cells, reduced hemoglobin levels, and showed a pronounced normoblastosis, Hi stological analyses of bone marrow, spleen, and liver showed a decreas e in both erythroid progenitors and mature red blood cells. Mutant fet al liver cells behaved normally in in vitro hematopoietic colony-formi ng assays but generated an anemia when transplanted into irradiated C. B.-17 SCID mice. Furthermore, reconstitution of the white cell compart ment of SCID mice by mutant fetal liver cells was less complete than t hat observed with a mixed population of wild-type and heterozygous fet al liver cells. Primary embryo fibroblasts from mutant mice were compl etely resistant to ecotropic retrovirus infection. Thus, mCAT-1 not on ly appears to be the sole receptor for a group of murine ecotropic ret roviruses associated with hematological disease but also plays a criti cal role in both hematopoiesis and growth control during mouse develop ment.