Regulated control by granulocyte-macrophage colony-stimulating factor AU-rich element during mouse embryogenesis

In vitro studies have indicated that the granulocyte-macrophage colony-stim ulating factor (GM-CSF) gene expression is regulated at the posttranscripti onal level by the AU-rich element (ARE) sequence present in its 3 ' untrans lated region (UTR). This study investigated the importance of the ARE in th e control of GM-CSF gene expression in vivo. For this purpose, transgenic m ice bearing GM-CSF gene constructs containing or lacking the ARE (GM-CSF AU (+) or GM-CSF AU(-), respectively) were generated. Both transgenes were und er the transcriptional control of the immediate early promoter of the cytom egalovirus (CMV) to ensure their early, widespread, and constitutive expres sion. The regulation imposed by the ARE was revealed by comparing transgene expression at day 14 of embryonic development (E14); only the ARE-deleted but not the ARE-containing construct was expressed. Although GM-CSF AU(+) e mbryos were phenotypically normal, overexpression of GM-CSF in E14 GM-CSF A U(-) embryos led to severe hematopoietic alterations such as abnormal proli feration of granulocytes and macrophages accompanied by an increased number of peroxidase-expressing cells, their putative progenitor cells. These abn ormalities compromise development because no viable GM-CSF AU(-) transgenic pups could be obtained. Surprisingly, by E18, significant accumulation of transgene messenger RNA was also observed in GM-CSF AU+ embryos leading to similar phenotypic abnormalities. Altogether, these observations reveal tha t GM-CSF ARE is a developmentally controlled regulatory element and highlig ht the consequences of GM-CSF overexpression on myeloid cell proliferation and differentiation. (C) 2001 by The American Society of Hematology.