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 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.
Perkins
C P
CP
Department of Molecular Genetics, Amgen, Inc., Thousand Oaks, California 91320, USA. cperkins@amgen.com
Mar
V
V
Shutter
J R
JR
del Castillo
J
J
Danilenko
D M
DM
Medlock
E S
ES
Ponting
I L
IL
Graham
M
M
Stark
K L
KL
Zuo
Y
Y
Cunningham
J M
JM
Bosselman
R A
RA
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
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011991:Receptors, Virus; C070506:ecotropic murine leukemia virus receptor