Identification of Basp1 as a novel angiogenesis-regulating gene by multi-model system studies.
Animals
Cell Movement
Corneal Neovascularization
/ genetics
Genome-Wide Association Study
Humans
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Models, Biological
Morphogenesis
Neovascularization, Pathologic
/ genetics
Nerve Tissue Proteins
/ genetics
Repressor Proteins
/ genetics
Wnt Signaling Pathway
Zebrafish
Wilm’s tumor (WT1)
Wnt/β-catenin pathway
angiogenesis
basic fibroblast growth factor (bFGF)
brain abundant membrane attached signal protein 1 (BASP1)
corneal micropocket neovascularization (CoNV)
efficient mixed model association (EMMA)
genome-wide association (GWAS)
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
13
01
2021
received:
17
08
2020
accepted:
15
01
2021
entrez:
26
4
2021
pubmed:
27
4
2021
medline:
20
7
2021
Statut:
ppublish
Résumé
We have previously used the genetic diversity available in common inbred mouse strains to identify quantitative trait loci (QTLs) responsible for the differences in angiogenic response using the corneal micropocket neovascularization (CoNV) assay. Employing a mouse genome-wide association study (GWAS) approach, the region on chromosome 15 containing Basp1 was identified as being significantly associated with angiogenesis in inbred strains. Here, we developed a unique strategy to determine and verify the role of BASP1 in angiogenic pathways. Basp1 expression in cornea had a strong correlation with a haplotype shared by mouse strains with varied angiogenic phenotypes. In addition, inhibition of BASP1 demonstrated a dosage-dependent effect in both primary mouse brain endothelial and human microvascular endothelial cell (HMVEC) migration. To investigate its role in vivo, we knocked out basp1 in transgenic kdrl:zsGreen zebrafish embryos using a widely adopted CRISPR-Cas9 system. These embryos had severely disrupted vessel formation compared to control siblings. We further show that basp1 promotes angiogenesis by upregulating β-catenin gene and the Dll4/Notch1 signaling pathway. These results, to the best of our knowledge, provide the first in vivo evidence to indicate the role of Basp1 as an angiogenesis-regulating gene and opens the potential therapeutic avenues for a wide variety of systemic angiogenesis-dependent diseases.
Identifiants
pubmed: 33899275
doi: 10.1096/fj.202001936RRR
pmc: PMC8218237
mid: NIHMS1664470
doi:
Substances chimiques
BASP1 protein, human
0
Membrane Proteins
0
Nerve Tissue Proteins
0
Repressor Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21404Subventions
Organisme : NIH HHS
ID : R24 OD017870
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY012726
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2021 Federation of American Societies for Experimental Biology.
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