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Inactivation of G‐protein coupled receptor 48 impairs definitive erythropoiesis at midgestation through downregulation of ATF4 pathway
Author(s) -
Luo Weijia,
Song Huiping,
Luo Jian,
Weng Jingsheng,
li Dali,
Liu Mingyao
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.812.1
Subject(s) - erythropoiesis , biology , endocrinology , medicine , creb , receptor , paracrine signalling , transcription factor , microbiology and biotechnology , anemia , genetics , gene
G protein‐coupled receptors (GPCRs), one of the most versatile groups of cell surface receptors, can recognize specific ligands from neural, hormonal, and paracrine organs and regulate cell growth, proliferation and differentiation. Gpr48/LGR4 is a recently identified orphan GPCR with unknown functions. To reveal the functions of Gpr48 in vivo , we generated Gpr48 −/− mice and found that Gpr48 −/− fetuses displayed transient anemia during midgestation and abnormal definitive erythropoiesis. The dramatic decrease of definitive erythroid precursors (Ter119 pos population) in Gpr48 −/− fetal liver at E13.5 was confirmed by histological analysis and blood smear assays. Real‐time PCR analyses showed that in Gpr48 −/− mice both adult hemoglobin α and β chains were decreased while embryonic hemoglobin chains (ξ, βH1 and Єy) were increased, providing another evidence for the impairment of definitive erythropoiesis. Proliferation but not apoptosis was deficient in Gpr48 −/− fetal liver, associated with the down‐regulation of c‐Myc and cyclin D1 expression levels. Furthermore, ATF4, a key transcription factor in erythropoiesis, was downregulated in Gpr48 −/− fetal livers during midgestation stage through cAMP‐PKA‐CREB pathway, suggesting that Gpr48 regulated definitive erthropoiesis through ATF4‐mediated definitive erythropoiesis.