TY - JOUR
T1 - Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway
AU - Song, Huiping
AU - Luo, Jian
AU - Luo, Weijia
AU - Weng, Jinsheng
AU - Wang, Zhiqiang
AU - Li, Baoxing
AU - Li, Dali
AU - Liu, Mingyao
PY - 2008/12/26
Y1 - 2008/12/26
N2 - 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 (Ter119pos 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 (ζ, βH1, and εy) were increased, providing another evidence for the impairment of definitive erythropoiesis. Furthermore, proliferation was suppressed in Gpr48-/- fetal liver with decreased c-Myc and cyclin D1 expression, whereas apoptosis was unaffected. ATF4, a key transcription factor in erythropoiesis, was downregulated in Gpr48-/- fetal livers during midgestation stage through the cAMP-PKA-CREB pathway, suggesting that Gpr48 regulated definitive erythropoiesis through ATF4-mediated definitive erythropoiesis.
AB - 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 (Ter119pos 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 (ζ, βH1, and εy) were increased, providing another evidence for the impairment of definitive erythropoiesis. Furthermore, proliferation was suppressed in Gpr48-/- fetal liver with decreased c-Myc and cyclin D1 expression, whereas apoptosis was unaffected. ATF4, a key transcription factor in erythropoiesis, was downregulated in Gpr48-/- fetal livers during midgestation stage through the cAMP-PKA-CREB pathway, suggesting that Gpr48 regulated definitive erythropoiesis through ATF4-mediated definitive erythropoiesis.
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U2 - 10.1074/jbc.M800721200
DO - 10.1074/jbc.M800721200
M3 - Article
C2 - 18955481
AN - SCOPUS:61449197690
SN - 0021-9258
VL - 283
SP - 36687
EP - 36697
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -