Molecular pathways regulating pro-migratory effects of Hedgehog signaling.
The Hedgehog proteins play a crucial role in metazoan embryo development. Constitutive activation of the pathway is associated with multiple types of cancer. Recent experimental data suggest involvement of Hedgehog signaling in vascular remodeling, germ cell migration, and axon guidance. The molecular mechanisms underlying these effects remain elusive. Here we show that yolk sac-derived endothelial cells and embryonic fibroblasts can directly respond to the Hedgehog signal by increased migration in an in vitro scratch (wound) assay. We also identify Hedgehog transcriptional target genes in these cells, many of which participate in cell migration, axon guidance, and angiogenesis processes. Inhibition of one such molecular pathway, neuropilin-flavomonooxygenase, blocks Hedgehog-induced cell migration. These findings suggest that Hedgehog signaling directly affects embryonic endothelial and fibroblast cell migration via molecules and pathways known to regulate cell migration in response to a variety of environmental cues.
Hochman
Eldar
E
Research Section of Childhood Malignancies, Sheba Cancer Research Center, Safra Children Hospital, Sheba Medical Center and Faculty of Medicine, Tel-Aviv University, Tel Hashomer 52621, Israel.
Castiel
Asher
A
Jacob-Hirsch
Jasmine
J
Amariglio
Ninnette
N
Izraeli
Shai
S
D000818:Animals; D001369:Axons / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D046228:Microarray Analysis; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000502:physiology; D039921:Neuropilins / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D015017:Yolk Sac / Q000166:cytology / Q000378:metabolism
D015415:Biomarkers; D053823:Hedgehog Proteins; D039921:Neuropilins; D012333:RNA, Messenger; C509239:SHH protein, human; C465570:Shh protein, mouse