OBJECTIVE. Molecular pathways governing blood vessel patterning are vital to vertebrate development. Because of their ability to counteract proangiogenic factors, antiangiogenic secreted Sema3 (class 3 semaphorins) control embryonic vascular morphogenesis. However, if and how Sema3 may play a role in the control of extraembryonic vascular development is presently unknown. APPROACH AND RESULTS: By characterizing genetically modified mice, here, we show that surprisingly Sema3F acts instead as a selective extraembryonic, but not intraembryonic proangiogenic cue. Both in vivo and in vitro, in visceral yolk sac epithelial cells, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, a transcription factor that drives the expression of proangiogenic genes, such as the microRNA cluster 17/92. In Sema3f-null yolk sacs, the transcription of Myc-regulated microRNA 17/92 cluster members is impaired, and the synthesis of Myc and microRNA 17/92 foremost antiangiogenic target Thbs1 (thrombospondin 1) is increased, whereas Vegf (vascular endothelial growth factor) signaling is inhibited in yolk sac endothelial cells. Consistently, exogenous recombinant Sema3F inhibits the phosphorylation-dependent degradation of Myc and the synthesis of Thbs1 in mouse F9 teratocarcinoma stem cells that were in vitro differentiated in visceral yolk sac epithelial cells. Sema3f-/- mice placentas are also highly anemic and abnormally vascularized. CONCLUSIONS: Sema3F functions as an unconventional Sema3 that promotes extraembryonic angiogenesis by inhibiting the Myc-regulated synthesis of Thbs1 in visceral yolk sac epithelial cells.

Sema3F (Semaphorin 3F) Selectively Drives an Extraembryonic Proangiogenic Program

REGANO, DONATELLA;VISINTIN, ALESSIA;CLAPERO, FABIANA;BUSSOLINO, Federico;VALDEMBRI, Donatella;MAIONE, FEDERICA;SERINI, Guido
;
GIRAUDO, Enrico
Co-last
2017-01-01

Abstract

OBJECTIVE. Molecular pathways governing blood vessel patterning are vital to vertebrate development. Because of their ability to counteract proangiogenic factors, antiangiogenic secreted Sema3 (class 3 semaphorins) control embryonic vascular morphogenesis. However, if and how Sema3 may play a role in the control of extraembryonic vascular development is presently unknown. APPROACH AND RESULTS: By characterizing genetically modified mice, here, we show that surprisingly Sema3F acts instead as a selective extraembryonic, but not intraembryonic proangiogenic cue. Both in vivo and in vitro, in visceral yolk sac epithelial cells, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, a transcription factor that drives the expression of proangiogenic genes, such as the microRNA cluster 17/92. In Sema3f-null yolk sacs, the transcription of Myc-regulated microRNA 17/92 cluster members is impaired, and the synthesis of Myc and microRNA 17/92 foremost antiangiogenic target Thbs1 (thrombospondin 1) is increased, whereas Vegf (vascular endothelial growth factor) signaling is inhibited in yolk sac endothelial cells. Consistently, exogenous recombinant Sema3F inhibits the phosphorylation-dependent degradation of Myc and the synthesis of Thbs1 in mouse F9 teratocarcinoma stem cells that were in vitro differentiated in visceral yolk sac epithelial cells. Sema3f-/- mice placentas are also highly anemic and abnormally vascularized. CONCLUSIONS: Sema3F functions as an unconventional Sema3 that promotes extraembryonic angiogenesis by inhibiting the Myc-regulated synthesis of Thbs1 in visceral yolk sac epithelial cells.
2017
37
9
1710-1721
1721
http://atvb.ahajournals.org/
angiogenesis modulating agents; mice; myc; semaphorins; thrombospondins; yolk sac; Animals; Cell Line, Tumor; Embryonal Carcinoma Stem Cells; Endothelial Cells; Epithelial Cells; Female; Gene Expression Regulation, Developmental; Genotype; Gestational Age; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Nerve Tissue Proteins; Phenotype; Phosphorylation; Placenta; Pregnancy; Proteolysis; Proto-Oncogene Proteins c-myc; Signal Transduction; Thrombospondin 1; Vascular Endothelial Growth Factor A; Yolk Sac; Neovascularization, Physiologic; Cardiology and Cardiovascular Medicine
Regano, Donatella; Visintin, Alessia; Clapero, Fabiana; Bussolino, Federico; Valdembri, Donatella; Maione, Federica; Serini, Guido; Giraudo, Enrico
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1647888
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