Mice that lack activity of αvβ6- and αvβ8-integrins reproduce the abnormalities of<i>Tgfb1</i>- and<i>Tgfb3</i>-null mice

Aluwihare, Poshala; Mu, Zhenyu; Zhao, Zhicheng; Yu, David C.; Weinreb, Paul H.; Horan, Gerald; Violette, Shelia M.; Munger, John S.

doi:10.1242/jcs.035246

Cited by 190 publications

(183 citation statements)

References 49 publications

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“…Indeed, the only other well-defined example of a non-cell-autonomous role played by integrins in vascular development involves integrin αvβ8 in the CNS and retina, where failure to activate latent ECM-bound TGF-β was an underlying cause of the observed vascular defects (35,36). Interestingly, the palate defect in the Pitx1-cre; Itgb1 f/f embryos phenocopies double-knockouts of integrin β6/β8 and single-knockouts of TGF-β3, suggesting integrin β1-dependent TGF-β signaling in the palate (37,38).…”

Section: Discussionmentioning

confidence: 99%

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Scully

Skowronska‐Krawczyk

Krawczyk

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin β1 before the onset of angiogenesis resulted in failure of invading endothelial cells to recruit pericytes efficiently, whereas deletion later in embryogenesis led to decreased vascular density and lumen formation. In both cases, lack of epithelial integrin β1 was associated with a complete absence of vasculature in the pituitary gland at birth. Within pituitary epithelial cells, integrin β1 directs a large transcriptional program that includes components of the extracellular matrix and associated signaling factors that are linked to the observed non-cell-autonomous effects on angiogenesis. We conclude that epithelial integrin β1 functions as a critical and canonical regulator of developmental angiogenesis in the pituitary gland, thus providing insight into the long-standing systems biology conundrum of how vascular invasion is coordinated with tissue development.angiogenesis | integrin β1 | pituitary gland | mice

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Section: Discussionmentioning

confidence: 99%

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Scully

Skowronska‐Krawczyk

Krawczyk

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the 8 RGD-binding integrins, only avb6 and avb8 appear to be required for TGF-b1 activation at this stage, at least in regard to phenotypes in TGF-b1-deficient mice. Specifically, Itgb8 -/ -mice treated perinatally with an antibody that blocks avb6 develop the immunological features of Tgfb1 -/ -mice (severe multiorgan inflammation and absence of Langerhans cells), and Itgb6 -/ -;Itgb8 -/ -mice have a high incidence of cleft palate, the main finding in TGF-b3-null mice (Aluwihare et al 2009). Conversely, Tgfb1 RGE/RGE ;Tgfb3 -/ -mice are all born with brain hemorrhage, the only phenotype in mice lacking avb8 that is not seen in mice lacking just TGF-b1 or TGF-b3 (Mu et al 2008).…”

Section: Redundancy Among Tgf-b Isoforms and Integrin Activatorsmentioning

confidence: 99%

“…The phenotypes of avb6-and/or avb8-deficient mice (Aluwihare et al 2009) and Tgfb1 RGE/RGE mice (Yang et al 2007) indicate that integrin-mediated TGF-b activation is required for developmental events in angiogenesis, the immune system, and the palate. Fibrosis and injury models show that avb6 is needed to activate TGF-b on the short time scales of these models.…”

Section: Are There Other Modes Of Tgf-b Activation?mentioning

confidence: 99%

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

Munger¹,

Sheppard²

2011

Cold Spring Harbor Perspectives in Biology

316

275

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The growth factor TGF-b is secreted in a latent complex consisting of three proteins: TGF-b, an inhibitor (latency-associated protein, LAP, which is derived from the TGF-b propeptide) and an ECM-binding protein (one of the latent TGF-b binding proteins, or LTBPs). LTBPs interact with fibrillins and other ECM components and thus function to localize latent TGF-b in the ECM. LAP contains an integrin-binding site (RGD), and several RGD-binding integrins are able to activate latent TGF-b through binding this site. Mutant mice defective in integrin-mediated activators, and humans and mice with fibrillin gene mutations, show the critical role of ECM and integrins in regulating TGF-b signaling.

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“…(In this study, the cardiac interventricular septum and atrioventricular cushions were poorly developed in mutant embryos compared with controls, but it was not possible to formally investigate VSDs because the normal ventricular septum is still remodelling at E13.) Mice without one of the TGFb ligands (as seen in TGFb2, TGFb3, and certain TGFb1 KO mice) can develop to birth; this was recently shown to be due to ligand redundancy, because mice carrying mutations in both Tgfb1 and Tgfb3 genes show cerebral hemorrhage from E11.5 and subsequent embryonic lethality (Mu et al, 2008;Aluwihare et al, 2009). Interestingly, mice with mutations in alpha-V or beta-8 integrins also develop cerebral haemorrhage (Bader et al, 1998;Zhu et al, 2002).…”

Section: (Asterisk) Efmentioning

confidence: 99%

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

Robson

Allinson

Anderson

et al. 2010

Developmental Dynamics

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TGFb signalling is required for normal cardiac development. To investigate which cell types are involved, we used mice carrying a floxed Type II TGFb receptor (Tgfbr2fl) allele and Cre-lox genetics to deplete this receptor in different regions of the heart. The three target tissues and corresponding Cre transgenic lines were atrioventricular myocardium (using cGata6-Cre), ventricular myocardium (using Mlc2v-Cre), and vascular endothelium (using tamoxifen-activated Cdh5(PAC)-CreERT2). Spatio-temporal Cre activity in each case was tracked via lacZ activation from the Rosa26R locus. Atrioventricular-myocardial-specific Tgfbr2 knockout (KO) embryos had short septal leaflets of the tricuspid valve, whereas ventricular myocardial-specific KO embryos mainly exhibited a normal cardiac phenotype. Inactivation of Tgfbr2 in endothelial cells from E11.5 resulted in deficient ventricular septation, accompanied by haemorrhage from cerebral blood vessels. We conclude that TGFb signalling through the Tgfbr2 receptor, in endothelial cells, plays an important role in cardiac development, and is essential for cerebral vascular integrity. Developmental Dynamics 239:2435-2442,

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Mice that lack activity of αvβ6- and αvβ8-integrins reproduce the abnormalities ofTgfb1- andTgfb3-null mice

Abstract: SummaryMice that lack activity of αvβ6-and αvβ8-integrins reproduce the abnormalities of Tgfb1-and Tgfb3-null mice

Cited by 190 publications

References 49 publications

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

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