Rescue of the embryonic lethal hematopoietic defect reveals a critical role for GATA-2 in urogenital development

Mutations resulting in embryonic or early postnatal lethality could mask th e activities of any gene in unrelated and temporally distinct developmental pathways. Targeted inactivation of the transcription factor GATA-2 gene le ads to mid-gestational death as a consequence of hematopoietic failure. We show here that a 250 kbp GATA-2 yeast artificial chromosome (YAC) is expres sed strongly in both the primitive and definitive hematopoietic compartment s, while two smaller YACs are not. This largest YAC also rescues hematopoie sis in vitro and in vivo, thereby localizing the hematopoietic regulatory c is element(s) to between 100 and 150 kbp 5' to the GATA-2 structural gene. Introducing the YAC transgene into the GATA-2(-/-) genetic background allow s the embryos to complete gestation; however, newborn rescued pups quickly succumb to lethal hydro-ureternephrosis, and display a complex array of gen itourinary abnormalities. These findings reveal that GATA-2 plays equally v ital roles in urogenital and hematopoietic development.