Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

Abstract

SummaryIn briefThe 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.HighlightsBmp9 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.

Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors

“…Knowing that Alk1 -depleted HHT mouse models display hypersprouting and increased vascular density in their developing retinas [ 53 ], it is plausible that suppressed upregulation of LFNG by BMP9 in the presence of ALK1 -mutations might be contributing to this phenotype by mitigating Dll4 activation. Interestingly, during the submission of this work, a preprint by Ristori et al that also highlighted a crosstalk between BMP9 and LFNG in regulating Notch signaling was deposited in BioRxiv [ 54 ].…”

Polarity-JaM: An image analysis toolbox for cell polarity, junction and morphology quantification

“…The extracted data can be stitched together by label identification (59). This will inform computational models, including vertex models (37), but also the cellular Potts model (32,60) or agent-based models (61,62), which require a broad base of accurate quantitative data. Mechanistically, this will also help predict motion from static biomedical images, which is an interesting avenue for future research with a wide range of applications.…”