PUBLICATION
Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations
- Authors
- Li, W., Tran, V., Shaked, I., Xue, B., Moore, T., Lightle, R., Kleinfeld, D., Awad, I.A., Ginsberg, M.H.
- ID
- ZDB-PUB-210521-4
- Date
- 2021
- Source
- eLIFE 10: (Journal)
- Registered Authors
- Keywords
- developmental biology, zebrafish
- MeSH Terms
-
- Muscle Proteins/genetics*
- Muscle Proteins/metabolism
- Disease Models, Animal
- Mosaicism
- Brain/blood supply*
- PubMed
- 34013885 Full text @ Elife
Abstract
Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to induce mosaic inactivation of zebrafish ccm2 resulting in a novel lethal multi-cavernous lesion in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic those that mediate intussusceptive angiogenesis; however, in contrast to the normal process, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resultant aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires the flow-regulated transcription factor KLF2; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe a zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.
Genes / Markers
Figure Gallery (16 images)
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping