Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor β signaling

Abstract

A growing number of integral inner nuclear membrane (INM) proteins have been implicated in diverse cellular functions. Man1, an INM protein, has recently been shown to regulate transforming growth factor (Tgf) ␤ superfamily signaling by interacting with receptor-associated Smads. However, the in vivo roles of Man1 have not been fully characterized. Here, we show that Man1 regulates vascular remodeling by analyzing Man1-deficient embryos lacking the Smad interacting domain. Man1-deficient embryos die at midgestation because of defects in embryonic vasculature; the primary capillary plexus forms, but subsequent remodeling is perturbed. It has been proposed that the angiogenesis process is divided into two balanced phases, the activation and resolution/maturation phases, both of which are regulated by Tgf␤1. We have demonstrated, in Man1-deficient embryos, the expression of Tgfb1 is upregulated and Smad2/3 signaling is abnormally activated, resulting in increased extracellular matrix deposition, a hallmark of the resolution phase of angiogenesis. We have also showed that the recruitment of mural cells to the vascular wall is severely disturbed in mutants, which may lead to disruption of intercellular communication between endothelial and mural cells required for proper vascular remodeling. These results have revealed a novel role for Man1 in angiogenesis and provide the first evidence that vascular remodeling can be regulated at the INM through the interaction between Man1 and Smads.

Man1, an inner nuclear membrane protein, regulates left–right axis formation by controlling nodal signaling in a node‐independent manner

“…In the course of analyzing Man1 ⌬/⌬ embryos, we found that most of the mutant embryos (31 of 32) had pericardial edema (Ishimura et al, 2006), suggesting that they had defective heart morphogenesis. We investigated the gross morphology of Man1…”

“…In cultured cells, overexpression of MAN1 inhibits TGF␤-responsive reporter activation and antagonizes the arrest of TGF␤-induced cell proliferation. In the Xenopus embryo, overexpression of XMAN1 inhibits dorsal mesoderm induction by TGF␤/activin/Nodal signaling (Ishimura et al, 2006).…”

“…Our research group and another group investigated the consequences of Man1 deficiency using an embryonic stem (ES) cell line containing a gene-trap insertion into the Man1 locus (Ishimura et al, 2006;Cohen et al, 2007). Man1 homozygous mutants died during early organogenesis because of defective vascular development.…”

“…In Man1-deficient embryos, the regulation of SMAD signaling is perturbed probably because of the lack of the SMAD-interacting domain (Ishimura et al, 2006;Cohen et al, 2007). The nuclear phosphoSMAD2 signal increases in mutant embryos and MEFs, indicating that SMAD2/3 signaling is enhanced in Man1-deficient embryos.…”

Tissue-Specific Defects Are Caused by Loss of the Drosophila MAN1 LEM Domain Protein

“…GT , showed that homozygous mutants die during embryogenesis (Ishimura et al 2006;Cohen et al 2007). The phenotypes of Man1 GT embryos suggest that lethality was due to hyperactivation of the TGF-b/BMP signaling pathway, resulting in an increased nuclear accumulation of phosphorylated Smad2/3 and changes in Smad target gene expression that increase extracellular matrix deposition and altered vascular remodeling.…”