The orphan G-protein coupled receptor 182 is a negative regulator of definitive hematopoiesis through leukotriene B4 signaling
2020
The
G protein-coupled receptor 182 (GPR182) is an orphan GPCR,
the expression of which is enriched in embryonic endothelial cells
(ECs). However, the physiological role and molecular mechanism of
action of GPR182 are unknown. Here, we show that GPR182 negatively
regulates definitive hematopoiesis in zebrafish and mice. In zebrafish, gpr182 expression is enriched in the hemogenic endothelium
(HE), and gpr182–/– display
an increased expression of HE and hematopoietic stem cell (HSC) marker
genes. Notably, we find an increased number of myeloid cells in gpr182–/– compared to wild-type.
Further, by time-lapse imaging of zebrafish embryos during the endothelial-to-hematopoietic
transition, we find that HE/HSC cell numbers are increased in gpr182–/– compared to wild-type. GPR182–/– mice also exhibit an
increased number of myeloid cells compared to wild-type, indicating
a conserved role for GPR182 in myelopoiesis. Using cell-based small
molecule screening and transcriptomic analyses, we further find that
GPR182 regulates the leukotriene B4 (LTB4) biosynthesis pathway. Taken
together, these data indicate that GPR182 is a negative regulator
of definitive hematopoiesis in zebrafish and mice, and provide further
evidence for LTB4 signaling in HSC biology.
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