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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1281-1288
PLENARY PAPER
Regulated control by granulocyte-macrophage colony-stimulating
factor AU-rich element during mouse embryogenesis
Laurent Houzet,
Dominique Morello,
Patrick Defrance,
Pascale Mercier,
Georges Huez, and
Véronique Kruys
From the Laboratoire de Chimie Biologique, Institut de
Biologie et de Médecine Moléculaires, Université
Libre de Bruxelles, Gosselies, Belgium; Centre de Biologie du
Développement, CNRS UMR 5547, Université Paul Sabatier,
Toulouse, France; and Service Transgenèse, Institut de
Pharmacologie et Biologie Structurale, CNRS UMR 5089, Toulouse, France.
In vitro studies have indicated that the granulocyte-macrophage
colony-stimulating factor (GM-CSF) gene expression is regulated at the
posttranscriptional level by the AU-rich element (ARE) sequence present
in its 3' untranslated region (UTR). This study investigated the
importance of the ARE in the control of GM-CSF gene expression in vivo.
For this purpose, transgenic mice bearing GM-CSF gene constructs
containing or lacking the ARE (GM-CSF AU+ or GM-CSF
AU , respectively) were generated. Both transgenes were
under the transcriptional control of the immediate early promoter of
the cytomegalovirus (CMV) to ensure their early, widespread, and
constitutive expression. 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+ embryos were phenotypically
normal, overexpression of GM-CSF in E14 GM-CSF AU embryos
led to severe hematopoietic alterations such as abnormal proliferation
of granulocytes and macrophages accompanied by an increased number of
peroxidase-expressing cells, their putative progenitor cells. These
abnormalities 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 that
GM-CSF ARE is a developmentally controlled regulatory element and
highlight the consequences of GM-CSF overexpression on myeloid cell
proliferation and differentiation.
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