Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling.
Genetic screens in lower organisms, particularly those that identify modifiers of preexisting genetic defects, have been used successfully to order components of complex signaling pathways. To date, similar suppressor screens have not been used in vertebrates. To define the molecular pathways regulating platelet production, we have executed a large-scale modifier screen with genetically thrombocytopenic Mpl(-/-) mice by using N-ethyl-N-nitrosourea mutagenesis. Here we show that mutations in the c-Myb gene cause a myeloproliferative syndrome and supraphysiological expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling. This screen demonstrates the utility of large-scale N-ethyl-N-nitrosourea mutagenesis suppressor screens in mice for the simultaneous discovery and in vivo validation of targets for therapeutic discovery in diseases for which mouse models are available.
Carpinelli
Marina R
MR
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville VIC 3052, Australia.
Hilton
Douglas J
DJ
Metcalf
Donald
D
Antonchuk
Jennifer L
JL
Hyland
Craig D
CD
Mifsud
Sandra L
SL
Di Rago
Ladina
L
Hilton
Adrienne A
AA
Willson
Tracy A
TA
Roberts
Andrew W
AW
Ramsay
Robert G
RG
Nicola
Nicos A
NA
Alexander
Warren S
WS
D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D019070:Cell Lineage; D005260:Female; D005434:Flow Cytometry; D016153:Genes, Suppressor; D020570:Genes, myb; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology*; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction; D013926:Thrombopoietin / Q000378:metabolism*
D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin