Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

Arnold, Thomas D.; Niaudet, Colin; Pang, Mei-Fong; Siegenthaler, Julie A.; Gaengel, Konstantin; Jung, Bongnam; Ferrero, G.; Mukouyama, Yoh‐suke; Fuxe, Jonas; Akhurst, Rosemary J.; Betsholtz, Christer; Sheppard, Dean; Reichardt, Louis F.

doi:10.1242/dev.107193

Cited by 89 publications

(104 citation statements)

References 79 publications

(119 reference statements)

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“…Our data support the idea that there are distinct tissue and temporal context-dependent requirements for specific integrin heterodimers in vascular development (11). 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: Discussionsupporting

confidence: 83%

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: Discussionsupporting

confidence: 83%

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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“…Cerebral angiogenic growth and barriergenesis are modulated by neuroepithelial cues that activate endothelial signaling cascades (Hagan and Ben-Zvi, 2014). These include canonical Wnt or Wnt/β-catenin signaling, which promotes both aspects of vascular development specifically in the central nervous system (CNS), and global regulators of angiogenic growth that have positive (VEGF and SDF1) or negative (Notch and TGF-β) roles (Arnold et al, 2014;Bussmann et al, 2011;Fujita et al, 2011;Gridley, 2010;Larrivee et al, 2012;Mackenzie and Ruhrberg, 2012;Masckauchan and Kitajewski, 2006;Reis and Liebner, 2013). Reck (reversion-inducing cysteine-rich protein with Kazal motifs) is a dimeric multi-domain glycosylphosphatidylinositol (GPI)-anchored protein isolated as a tumor suppressor whose overexpression normalizes the aberrant morphology of transformed fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Reck enables cerebrovascular development by promoting canonical Wnt signaling

et al. 2015

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The cerebral vasculature provides the massive blood supply that the brain needs to grow and survive. By acquiring distinctive cellular and molecular characteristics it becomes the blood-brain barrier (BBB), a selectively permeable and protective interface between the brain and the peripheral circulation that maintains the extracellular milieu permissive for neuronal activity. Accordingly, there is great interest in uncovering the mechanisms that modulate the formation and differentiation of the brain vasculature. By performing a forward genetic screen in zebrafish we isolated no food for thought (nft y72 ), a recessive late-lethal mutant that lacks most of the intracerebral central arteries (CtAs), but not other brain blood vessels. We found that the cerebral vascularization deficit of nft y72 mutants is caused by an inactivating lesion in reversion-inducing cysteine-rich protein with Kazal motifs [reck; also known as suppressor of tumorigenicity 15 protein (ST15)], which encodes a membrane-anchored tumor suppressor glycoprotein. Our findings highlight Reck as a novel and pivotal modulator of the canonical Wnt signaling pathway that acts in endothelial cells to enable intracerebral vascularization and proper expression of molecular markers associated with BBB formation. Additional studies with cultured endothelial cells suggest that, in other contexts, Reck impacts vascular biology via the vascular endothelial growth factor (VEGF) cascade. Together, our findings have broad implications for both vascular and cancer biology.

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“…Notably, when mice with a TGF-␤1 gene knock-in mutation that causes an RGE substitution of the RGD motif are crossed with TGF-␤3-deficient mice they die as a result of severe brain hemorrhage (51), recapitulating the phenotype of integrin ␤8-deficent mice. Given the similarities in phenotypes between ␣v␤8 integrin-deficient mice and TGF-␤1(RGE)/TGF-␤3 double mutant mice, ␣v␤8 integrin has been proposed to act as an "angiogenic switch" in the brain through TGF-␤ activation (52,53). Consistent with the role of ␣v␤8 integrin in TGF-␤1 activation, Yamazaki et al (54) reported that ␤8 integrin was specifically expressed by Schwann cells and involved in latent TGF-␤ activation in the bone marrow, thereby regulating hematopoietic stem cell hibernation.…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis of the Ligand Binding Specificity of αvβ8 Integrin

Ozawa

Sato

Imabayashi

et al. 2016

Journal of Biological Chemistry

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␣v␤8 is an integrin that recognizes an Arg-Gly-Asp (RGD) motif and interacts with fibronectin, vitronectin, and latent TGF-␤1. We comprehensively determined the binding activity of the ␣v␤8 integrin toward 25 secreted proteins having an RGD motif. The ␣v␤8 integrin strongly bound to latent TGF-␤1 but showed marginal activity for other RGD-containing proteins, including fibronectin and vitronectin. Site-directed mutagenesis of latent TGF-␤1 demonstrated that the high affinity binding of ␣v␤8 integrin to latent TGF-␤1 was defined by Leu-218 immediately following the RGD motif within the latency-associated peptide of TGF-␤1. Consistent with the critical role of Leu-218 in latent TGF-␤1 recognition by ␣v␤8 integrin, a 9-mer synthetic peptide containing an RGDL sequence strongly inhibited interactions of latent TGF-␤1 with ␣v␤8 integrin, whereas a 9-mer peptide with an RGDA sequence was ϳ60-fold less inhibitory. Because ␣v␤3 integrin did not exhibit strong binding to latent TGF-␤1 or distinguish between RGDL-and RGDA-containing peptides, we explored the mechanism by which the integrin ␤8 subunit defines the high affinity binding of latent TGF-␤1 by ␣v␤8 integrin. Production of a series of swap mutants of integrin ␤8 and ␤3 subunits indicated that the high affinity binding of ␣v␤8 integrin with latent TGF-␤1 was ensured by interactions between the Leu-218 residue and the ␤8 I-like domain, with the former serving as an auxiliary recognition residue defining the restricted ligand specificity of ␣v␤8 integrin toward latent TGF-␤1. In support of this conclusion, high affinity binding toward the ␣v␤8 integrin was conferred on fibronectin by substitution of its RGDS motif with an RGDL sequence.Integrins are a family of adhesion receptors that bind to a variety of extracellular ligands, typically cell adhesion proteins in the extracellular matrix (ECM).2 Integrins play mandatory roles in embryonic development and the maintenance of tissue architecture by providing essential links between cells and the ECM (1). Integrins are composed of two non-covalently associated subunits, termed ␣ and ␤. In mammals, 18 ␣ and 8 ␤ subunits have been identified, and combinations of these subunits give rise to at least 24 distinct integrin heterodimers, among which 18 isoforms function as ECM receptors. Based on their ligand binding specificities, ECM-binding integrins are classified into three major groups as follows: laminin-, collagen-, and Arg-Gly-Asp (RGD)-binding integrins (1, 2), of which the RGD-binding integrins have been most extensively investigated. The RGD-binding integrins include ␣5␤1, ␣8␤1, ␣IIb␤3, and ␣v-containing integrins, which interact with a variety of ECM ligands containing RGD motifs with distinct binding specificities.The integrin ␣v subunit was originally identified as a receptor for vitronectin (3). The ␣v-containing integrins are widely expressed on many cell types, including neural crest cells, glial cells, muscle cells, osteoclasts, epithelial cells, and vascular endothelial cells during embryonic development (4...

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Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

Cited by 89 publications

References 79 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

Reck enables cerebrovascular development by promoting canonical Wnt signaling

Molecular Basis of the Ligand Binding Specificity of αvβ8 Integrin

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