Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe
Year: 2026
Type: article
Abstract: In brief: The mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates the crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby regulating the endothelial cell behavior and temporal dynamics of their identity during sprouting angiogenesis. Highlights: Bmp9 upregulates the expression of LFng in endothelial cells.LFng regulates the temporal dynamics of tip/stalk selection and rearrangement.LFng indicated to play a role in hereditary hemorrhagic telangiectasia.Bmp9 and LFng mediate the endothelial cell-pericyte crosstalk.Bone Morphogenic Protein 9 (Bmp9), whose signaling through Activin receptor-like kinase 1 (Alk1) is involved in several diseases, has been shown to independently activate Notch target genes in an additive fashion with canonical Notch signaling. Here, by integrating predictive computational modeling validated with experiments, we uncover that Bmp9 upregulates Lunatic Fringe (LFng) in endothelial cells (ECs), and thereby also regulates Notch activity in an inter-dependent, multiplicative fashion. Specifically, the Bmp9-upregulated LFng enhances Notch receptor activity creating a much stronger effect when Dll4 ligands are also present. During sprouting, this LFng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement. Our results further indicate that LFng can play a role in Bmp9-related diseases and in pericyte-driven vessel stabilization, since we find LFng contributes to Jag1 upregulation in Bmp9-stimulated ECs; thus, Bmp9-upregulated LFng results in not only enhanced EC Dll4-Notch1 activation, but also Jag1-Notch3 activation in pericytes.
Source: Developmental Cell
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: American Heart Association, European Molecular Biology Organization, Boston University, Wellcome Trust, Francis Crick Institute, Alabama Humanities Alliance, Cancer Research UK, British Heart Foundation, European Commission, Academy of Finland, EMBO, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, China Scholarship Council, Svenska Kulturfonden, Åbo Akademi, National Institutes of Health, Horizon 2020 Framework Programme, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Medical Research Council, European Research Council, H2020 European Research Council, H2020 Marie Skłodowska-Curie Actions, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: G1110489107, G1269101333, G1767959753, G19609650, G2099028486, Investigating the crosstalk between Notch and YAP/TAZ in sprouting angiogenesis, G2531223261, Pyramidal neuron polarity decisions during migration and axonal outgrowth in the developing mammalian cerebral cortex, G2835847320, Multilayer mechanosignalling in vascular homeostasis-SIGNALSHEETS, G374036898, G4943370550, The integration of cell signalling and mechanical forces in vascular morphology, Deciphering morphogenetic cues encoded in cell shape, Deciphering morphogenetic cues encoded in cell shape, Melanoma vessel co-option in brain metastasis, Transcriptional control of the metabolic switch in angiogenesis, Local Regulation of Angiogenesis by Microenvironment, Notch signaling and adhesion regulation, G8894540129, G9000044433, G9000218596
OpenAlex ID: W7127990846