title: Anemia and perinatal death result from loss of the murine ecotropic retrovirus receptor mCAT-1.
abstract: The mCAT-1 gene encodes a basic amino acid transporter that also acts as the receptor for murine ecotropic leukemia viruses. Targeted mutagenesis in embryonic stem cells has been used to introduce a germ-line null mutation into this gene. This mutation removes a domain critical for virus binding and inactivates amino acid transport activity. Homozygous mutant pups generated from these cells were approximately 25% smaller 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. Histological analyses of bone marrow, spleen, and liver showed a decrease in both erythroid progenitors and mature red blood cells. Mutant fetal liver cells behaved normally in in vitro hematopoietic colony-forming assays but generated an anemia when transplanted into irradiated C.B.-17 SCID mice. Furthermore, reconstitution of the white cell compartment of SCID mice by mutant fetal liver cells was less complete than that observed with a mixed population of wild-type and heterozygous fetal liver cells. Primary embryo fibroblasts from mutant mice were completely resistant to ecotropic retrovirus infection. Thus, mCAT-1 not only appears to be the sole receptor for a group of murine ecotropic retroviruses associated with hematological disease but also plays a critical role in both hematopoiesis and growth control during mouse development.
authors.affiliation: Department of Molecular Genetics, Amgen, Inc., Thousand Oaks, California 91320, USA. cperkins@amgen.com
authors.forename: C P
authors.initials: CP
authors.lastname: Perkins
authors.forename: V
authors.initials: V
authors.lastname: Mar
authors.forename: J R
authors.initials: JR
authors.lastname: Shutter
authors.forename: J
authors.initials: J
authors.lastname: del Castillo
authors.forename: D M
authors.initials: DM
authors.lastname: Danilenko
authors.forename: E S
authors.initials: ES
authors.lastname: Medlock
authors.forename: I L
authors.initials: IL
authors.lastname: Ponting
authors.forename: M
authors.initials: M
authors.lastname: Graham
authors.forename: K L
authors.initials: KL
authors.lastname: Stark
authors.forename: Y
authors.initials: Y
authors.lastname: Zuo
authors.forename: J M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: R A
authors.initials: RA
authors.lastname: Bosselman
mesh_terms: D000740:Anemia / Q000151:congenital*; D000818:Animals; D000831:Animals, Newborn; D001853:Bone Marrow / Q000002:abnormalities; D002352:Carrier Proteins / Q000235:genetics*; D002452:Cell Count; D017690:Cell Transplantation; D015672:Erythroid Precursor Cells / Q000166:cytology; D005804:Genes, Lethal; D006410:Hematopoiesis / Q000235:genetics; D008099:Liver / Q000002:abnormalities; D016031:Liver Transplantation; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D011991:Receptors, Virus / Q000235:genetics*; D012190:Retroviridae / Q000254:growth & development*; D013154:Spleen / Q000002:abnormalities; D013234:Stem Cells
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011991:Receptors, Virus; C070506:ecotropic murine leukemia virus receptor