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 the activities of any gene in unrelated and temporally distinct developmental pathways. Targeted inactivation of the transcription factor GATA-2 gene leads to mid-gestational death as a consequence of hematopoietic failure. We show here that a 250 kbp GATA-2 yeast artificial chromosome (YAC) is expressed strongly in both the primitive and definitive hematopoietic compartments, while two smaller YACs are not. This largest YAC also rescues hematopoiesis in vitro and in vivo, thereby localizing the hematopoietic regulatory cis 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 allows the embryos to complete gestation; however, newborn rescued pups quickly succumb to lethal hydroureternephrosis, and display a complex array of genitourinary abnormalities. These findings reveal that GATA-2 plays equally vital roles in urogenital and hematopoietic development.