Regulator of G-protein signaling 18 controls megakaryopoiesis and the cilia-mediated vertebrate mechanosensory system.
RGS18 was originally identified as a R4 subfamily member of regulators of G-protein signaling (RGS) with specific expression in hematopoietic progenitors, myeloerythroid cells, and megakaryocytes, though its physiological role in hematopoiesis remained unknown. Here, we show that lentiviral RGS18 overexpression during differentiation of mouse Sca1(+) hematopoietic stem cells induced a 50% increase of megakaryocyte proliferation. RGS18 depletion in zebrafish results in thrombocytopenia, as 66 to 88% of the embryos lack thrombocytes after injection of an ATG or splice-blocking morpholino, respectively. These embryos have no defects in early hematopoiesis, erythropoiesis, or leukocyte number and migration. In addition, all RGS18 depleted embryos have curly tails and an almost absent response to acoustic stimuli. In situ hybridization in zebrafish, Xenopus, and mouse embryos shows RGS18 expression in thrombocytes and/or hematological tissues but also in brain and otic vesicles. RGS18 interferes with development of cilia in hair cells of the inner ear and neuromast cells. On the basis of literature evidence that RGS-R4 members interact with the G-protein-modulated Wnt/calcium pathway, Wnt5b- but not Wnt5a-depleted embryos phenocopy all RGS18 knockdown effects. In summary, our study is the first to show that RGS18 regulates megakaryopoiesis but also reveals its unexpected role in ciliogenesis, at least in lower vertebrates, via interference with Wnt signaling.
Center for Molecular and Vascular Biology, KU Leuven, Campus Gasthuisberg, O&N1, Herestraat 49, Box 911, 3000 Leuven, Belgium.
Sophie
S
Louwette
Veerle
V
Labarque
Christine
C
Wittevrongel
Chantal
C
Thys
Juriaan
J
Metz
Rik
R
Gijsbers
Zeger
Z
Debyser
Jef
J
Arnout
Chris
C
Van Geet
Kathleen
K
Freson
D000818:Animals; D001483:Base Sequence; D002923:Cilia / Q000502:physiology*; D017931:DNA Primers; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D040542:Mechanotransduction, Cellular; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D020710:RGS Proteins; D051153:Wnt Proteins / Q000378:metabolism
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020710:RGS Proteins; C422991:Rgs18 protein, mouse; D051153:Wnt Proteins; C468567:Wnt5b protein, mouse