Dataset Information

CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway.

ABSTRACT: The formation of the vascular system is essential for embryonic development and homeostasis. However, transcriptional control of this process is not fully understood. Here we report an evolutionarily conserved role for the transcription factor CASZ1 (CASTOR) in blood vessel assembly and morphogenesis. In the absence of CASZ1, Xenopus embryos fail to develop a branched and lumenized vascular system, and CASZ1-depleted human endothelial cells display dramatic alterations in adhesion, morphology, and sprouting. Mechanistically, we show that CASZ1 directly regulates Epidermal Growth Factor-Like Domain 7 (Egfl7). We further demonstrate that defects of CASZ1- or EGFL7-depleted cells are in part due to diminished RhoA expression and impaired focal adhesion localization. Moreover, these abnormal endothelial cell behaviors in CASZ1-depleted cells can be rescued by restoration of Egfl7. Collectively, these studies show that CASZ1 is required to directly regulate an EGFL7/RhoA-mediated pathway to promote vertebrate vascular development.

SUBMITTER: Charpentier MS

PROVIDER: S-EPMC3641863 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway.

Charpentier Marta S MS Christine Kathleen S KS Amin Nirav M NM Dorr Kerry M KM Kushner Erich J EJ Bautch Victoria L VL Taylor Joan M JM Conlon Frank L FL

Developmental cell 20130401 2

The formation of the vascular system is essential for embryonic development and homeostasis. However, transcriptional control of this process is not fully understood. Here we report an evolutionarily conserved role for the transcription factor CASZ1 (CASTOR) in blood vessel assembly and morphogenesis. In the absence of CASZ1, Xenopus embryos fail to develop a branched and lumenized vascular system, and CASZ1-depleted human endothelial cells display dramatic alterations in adhesion, morphology, a ...[more]

PMID: 23639441

Similar Datasets

Project description:ObjectiveMitogen-activated protein kinase pathways play an important role in neointima formation secondary to vascular injury, in part by promoting proliferation of vascular smooth muscle cells (VSMC). Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that activates multiple mitogen-activated protein kinase pathways and has been implicated in regulating proliferation in several cell types. However, the role of MLK3 in VSMC proliferation and neointima formation is unknown. The aim of this study was to determine the function of MLK3 in the development of neointimal hyperplasia and to elucidate the underlying mechanisms.Approach and resultsNeointima formation was analyzed after endothelial denudation of carotid arteries from wild-type and MLK3-deficient mice. MLK3 deficiency promoted injury-induced neointima formation and increased proliferation of primary VSMC derived from aortas isolated from MLK3-deficient mice compared with wild-type mice. Furthermore, MLK3 deficiency increased the activation of p63Rho guanine nucleotide exchange factor, RhoA, and Rho kinase in VSMC, a pathway known to promote neointimal hyperplasia, and reconstitution of MLK3 expression attenuated Rho kinase activation. Furthermore, cJun NH2-terminal kinase activation was decreased in MLK3-deficient VSMC, and proliferation of wild-type but not MLK3 knockout cells treated with a cJun NH2-terminal kinase inhibitor was attenuated.ConclusionsWe demonstrate that MLK3 limits RhoA activation and injury-induced neointima formation by binding to and inhibiting the activation of p63Rho guanine nucleotide exchange factor, a RhoA activator. In MLK3-deficient cells, activation of p63Rho guanine nucleotide exchange factor proceeds in an unchecked manner, leading to a net increase in RhoA pathway activation. Reconstitution of MLK3 expression restores MLK3/p63Rho guanine nucleotide exchange factor interaction, which is attenuated by feedback from activated cJun NH2-terminal kinase.

Dataset Information

CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway.

Publications

CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets