Current Opinion in Hematology:
VASCULAR BIOLOGY: Edited by Thomas F. Deuel
Transcriptional regulation of arterial differentiation via Wnt, Sox and Notch
Morini, Marco Francescoa; Dejana, Elisabettaa,b
aIFOM, FIRC Institute of Molecular Oncology
bDepartment of Biosciences, University of Milan, Milan, Italy
Correspondence to Elisabetta Dejana, IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy. Tel: +39 02574303234; e-mail: firstname.lastname@example.org
Purpose of review
The development of a functionally and anatomically correct vascular network is a complex phenomenon that requires the combined activity of different signaling pathways and transcription factors. Notch signaling activation, for instance, is crucial for arterial specification. Here, we discuss the current knowledge on how other signaling pathways cooperate with Notch to orchestrate arterial differentiation of embryonic and postnatal vasculature.
The role of Notch in vascular development and arterial differentiation is well known. However, it was found that canonical Wnt signaling may act upstream of Notch, upregulating Dll4 and inducing endothelial cells to acquire arterial characteristics. Furthermore, the transcription factor Sox17 may act as a link between Wnt and Notch in the induction of a correct arterio/venous differentiation.
In the past years, the research on vascular development was mostly focused on the mechanisms that regulate vessel growth. We now understand that in order to interfere with several vascular diseases (e.g. aneurysm, cerebral ischemia and stroke) or tumor vascularization, we need to understand the signals that direct arterio/venous specification. Here, we discuss the interplay between Notch, Wnt and Sox that exert a combined positive action on arterial differentiation.
A correct organization of the vascular network is required for the development and survival of multicellular organisms. In mice, from embryonic day (E)6.5 onward, vascular development takes place in the yolk sac and the embryo proper via two distinct mechanisms: vasculogenesis and angiogenesis [1,2]. The term vasculogenesis refers to the process of vascular development from mesoderm-derived endothelial precursor cells or angioblasts. These cells initially form structures called blood islands that subsequently reorganize into the so-called primitive vascular plexus that sustains the delivery of oxygen and nutrients to the developing tissues . Later on, when the heart starts to beat around E8.5, the primitive network of vessels undergoes a profound reshaping and expansion process called angiogenesis, defined as the growth of new vessels from preexisting ones [2,3]. This process is of particular importance given that the vascular system must now cope with the hemodynamic forces generated by the blood flow. For these reasons, vascular endothelial cells, lining the inner surface of blood vessels, need to differentiate from angioblasts to full blown arterial or venous endothelial cells. This complex process cannot be directed by a single transcription factor or even by a single family of transcription factors. On the contrary, in the last decades, we learned that endothelial cell differentiation could not occur without the coordinated interplay of different members of the E-twenty six, GATA and Kruppel-like factor families, that have been described in previous excellent reviews [1,4,5]. The aim of the present review is to highlight the recent findings that put sex determining region Y-box (Sox)17 transcription factor under the limelight for being a bridge between Wingless-related MMTV integration site (Wnt) and Notch signaling pathways in promoting arterial endothelial cell differentiation [6▪,7▪▪,8▪].
Wnt SIGNALING AND VASCULAR DEVELOPMENT
β-Catenin is a well known protein both for its function as a transcriptional co-activator and as a key member in adherens junction complex formation [9–11]. β-Catenin is composed of an N-terminal regulatory domain where phosphorylatable residues are located, 12 armadillo repeats required for interaction with binding partners and a C-terminal transactivation domain [10,12]. Although the pool of β-catenin residing at adherens junctions is considered to be stable, the cytosolic pool of β-catenin has a much shorter half-life in the absence of Wnt stimulation. Indeed, in resting conditions, β-catenin levels are kept in check by the so-called β-catenin destruction complex that is composed of adenomatous polyposis coli (APC), axin, dishevelled (Dsh), casein kinase 1 (CK1), glycogen synthase kinase 3 β (GSK3β) and β-transducin repeat containing protein (β-TrCP). Although axin and APC are thought to have mainly a scaffolding function, CK1, GSK3β and β-TrCP harbor enzymatic activity. The sequential N-terminal phosphorylation of β-catenin exerted by CK1 and GSK3β causes its β-TrCP-dependent ubiquitylation and proteasomal degradation [10,12,13]. Conversely, when Wnt ligands bind the low density lipoprotein receptor-related protein 5/6 (LRP5/6)/Frizzled heterodimeric complex, the activity of the β-catenin destruction complex is inhibited by the recruitment of axin to phosphorylated LRP5/6, thus inhibiting β-catenin ubiquitylation and degradation. As a result, cytoplasmic β-catenin is stabilized and part of it can enter the nucleus to promote the expression of Wnt-target genes such as Myc, Cyclin-D1 and Axin itself [10,12–15].
As β-catenin has been involved in a plethora of cellular functions, it is not surprising that straight β-catenin knockout animals show a dramatic phenotype and die during gastrulation [16,17]. Tampering with Wnt/β-catenin signaling in the vascular system leads to strong phenotypes as well, because both β-catenin deletion (loss-of-function, LOF) and stabilization (gain-of-function, GOF) have profound consequences on endothelial cell behavior [18–20]. Different Wnt ligands such as Wnt7a and Wnt7b have been shown to be required for the proper activation of canonical Wnt signaling in endothelial cells residing in the central nervous system (CNS), thus promoting blood–brain barrier (BBB) formation [21,22]. Indeed, the lack of both Wnt7a and Wnt7b in mice leads to embryonic lethality at E12.5 caused by a hemorrhaging phenotype specifically in the CNS . Similarly, β-catenin was also shown to be required for CNS vascularization because β-catenin deletion in endothelial cells strongly reduces the migration of endothelial cells inside the brain and spinal cord parenchyma and leads to vascular malformations . Moreover, the Norrin/Frizzled4 signaling axis was reported to be crucial for retinal vascular development and for the establishment of a functional BBB in the cerebellum [23,24]. β-Catenin-positive endothelial cells are present in several regions of the vascular tree starting from E9.5 both in the yolk sac and in the embryo proper . Interestingly, up to E15.5, the number of β-catenin-positive endothelial cells in the perineural vasculature is constantly high, while it undergoes a significant reduction from E15.5 to E17.5 onward . Cattelino et al. showed that from E10.5 onward endothelial-specific β-catenin LOF mice show vascular defects in yolk sac and in the head of the embryo that inevitably lead to death. At the ultrastructural level, the lack of β-catenin causes the formation of a thinner and often fenestrated layer of endothelial cells, whereas in-vitro β-catenin LOF endothelial cells display morphological alterations and increased paracellular permeability . Moreover, the activity of β-catenin is crucial for BBB formation and maintenance. Endothelial-specific β-catenin LOF mice show an impaired BBB formation and maturation due to reduced levels of the tight junction protein claudin-3 and increased levels of plasma lemma vescicle-associated protein, a protein associated with immature BBB. These molecular alterations have functional consequences on the control of BBB permeability . Likewise, Wnt7a/Wnt7b double knockout mice or endothelial-specific β-catenin knockout mice show an impairment in the expression of Glut-1, a glucose transporter, whose expression is a hallmark of mature BBB [21,22]. These findings indicate that the activity of the Wnt/β-catenin signaling axis is strictly required for the proper assembly of the BBB, and in general for the establishment of a functional vascular system [14,15].
As already mentioned, β-catenin GOF mice also show vascular defects. These mice die in utero because of the major defects in vascular development, such as reduced length and increased lumen size of intersomitic vessels, branching alterations and defects in the remodeling of small vessels in the perineural vascular plexus . Unexpectedly, it was found that β-catenin stabilization in endothelial cells impairs arteriovenous specification . In particular, veins acquire arterial markers while losing venous characteristics. These findings are reminiscent of the phenotype observed in the endothelial-specific Notch-signaling GOF mice . For instance, endothelial-specific Dll4 overexpression promotes the ectopic expression of arterial markers such as Notch1, Hey1, EphrinB2 and Connexin37 in the venous compartment and reduction of the venous marker EphB4 . Along the same line, many other members of the Notch signaling pathway have been found to be involved in the regulation of arterial specification [26–30]. β-Catenin GOF in endothelial cells leads to a strong activation of Notch signaling because of an increase in the expression of the Notch ligand Dll4, whose promoter is directly bound by β-catenin, and the Notch-dependent transcription factors Hey1 and Hey2. Treatment of β-catenin GOF mice with γ-secretase inhibitors that prevent the activation of Notch signaling rescues this phenotype by restoring the expression of the venous markers EphB4 and COUP-TFII, and restoring vascular remodeling . Thus, the effect of canonical Wnt signaling on ectopic arterial differentiation of veins is likely mediated by an increase in the Notch signaling.
In agreement with these results, Yamamizu et al. found that stimuli that increase nuclear Notch intracellular domain (NICD) staining, a marker of Notch signaling activation, simultaneously induce the expression of the arterial markers EphrinB2 and CXCR4 in endothelial cells. This effect is inhibited by a phosphatidylinositol 3 kinase inhibitor, but it is partially restored by blocking GSK3β β-catenin destruction complex, in line with the hypothesis that β-catenin has a role in arterial specification. The concomitant activation of Notch and Wnt signaling in the presence of VEGF led to a strong expression of arterial markers. The authors also reported that β-catenin, NICD and recombination signal binding protein for immunoglobulin kappa J region (RBP-J) form a complex in arterial endothelial cells, and that this complex binds the regulatory regions of arterial-specific genes such as EphrinB2, NRP1, Hes1, Dll4 and CXCR4. Taking all these findings together, we conclude that a cooperation between Wnt and Notch signaling pathways exists in endothelial cells and that the simultaneous activation of both is required for the successful arterial differentiation [14,32]. For the sake of completeness, a Notch-dependent regulation of Wnt signaling has been reported as well . Indeed, the Notch-regulated ankyrin repeat protein (Nrarp) is induced by Notch signaling activation in stalk cells, where it acts as a negative regulator of Notch signaling while promoting Wnt signaling activation by interacting with Lef-1. In this way, Nrarp increases the levels of the Wnt/β-catenin target gene Cyclin-D1, driving stalk cell proliferation.
Sox17 BRIDGES Wnt AND Notch SIGNALING TO PROMOTE ARTERIAL SPECIFICATION
Sox factors are a large family of transcription factors comprising approximately 30 members in vertebrates that have been subdivided into several subfamilies, termed A through H. Sox proteins are involved in many cellular functions and play crucial roles in many aspects of development . In particular, Sox7, Sox17 and Sox18 belong to the SoxF subgroup and have been previously linked to hematopoietic, vascular and lymphatic development and tumor angiogenesis [35–43,44▪].
The Koopman group [40,45] showed that Sox18 is expressed in a subpopulation of endothelial cells in the cardinal vein that will further differentiate in lymphatic endothelial cells. Sox18 directly binds Prox1 promoter and induces its expression. Prox1 is a key transcription factor for lymphatic differentiation. In zebrafish, double Sox18-morphants and Sox7-morphants present major problems in arteriovenous differentiation [39,46].
Recently, several publications elucidated the role of SoxF factors as promoters of Notch signaling in the context of arteriovenous specification by using different, complementary approaches [6▪,7▪▪,8▪]. Furthermore, Clarke et al.[8▪] demonstrated that Sox17 regulates the development and maintenance of hemogenic endothelium by activating Notch signaling.
Ye et al. and Corada et al.[6▪] found that Sox17 expression is downstream of canonical Wnt signaling. Moreover, Sox17 is restricted to embryonic and adult arteries [6▪]. Consistently, inducible endothelial-specific Sox17 deletion (Sox17iECKO) strongly impairs arterial specification. Constitutive Sox17iECKO mice die in utero due to the lack of large arteries and defective vascular patterning in the embryo and the yolk sac. The analysis of Sox17iECKO retinas showed a strong increase in tip cell number and vascular density in the growing front. Furthermore, in the absence of Sox17, arteries lose arterial markers and gain venous markers. Sox17 expression in endothelial cells promotes Notch signaling and upregulates Hey1, Dll4, Dll1 and Notch4. These findings place Sox17 in an important position to regulate arterial specification and maintenance.
The role of Sox17 in arterial differentiation is also underlined by Sacilotto et al.[7▪▪], who found that the arterial-specific expression of Dll4, one of the best characterized ligands of Notch receptors, is driven by a well conserved enhancer positioned within the third intron of Dll4. Murine Dll4 intron 3 enhancer is sufficient to drive reporter gene expression in zebrafish arteries, and the same holds true in transgenic mice expressing LacZ under the control of zebrafish Dll4 intron 3 enhancer. Of note, Dll4 intron 3 both in mouse and zebrafish contains several SoxF and RBP-J transcription factor binding sites that, if simultaneously mutated, completely abrogate arterial Dll4 expression. Along the same line, compound zebrafish morphants for Sox7, Sox18 and RBPJ undergo a dramatic impairment of Dll4 expression [7▪▪].
Evidence from different experimental systems that stem from vascular biology suggest that the relationship between Wnt signaling and Sox factors could be more complex than it was previously believed. Indeed, Sox transcription factors have been reported to modulate the signaling output of Wnt/β-catenin signaling in opposite ways. Sinner et al. demonstrated that in APCmin/+ colon carcinomas Sox17 and Sox4 are the most differentially regulated Sox transcription factors, Sox17 being the least expressed and Sox4 being the most upregulated, compared with normal gut samples. This is of particular interest given that Sox17 strongly inhibits Wnt signaling while Sox4 induces it . In addition, Sox17 is reported to form a complex with β-catenin and with several members of the TCF/LEF family of transcription factors, proving that Sox17 does not antagonize Wnt signaling by competing with β-catenin/TCF interaction. On the contrary, the authors show that Sox17 promotes the proteasomal degradation of β-catenin, TCF4 and LEF1. Sox17 mutants lacking either the N-terminus, which contains the high mobility group domain required to bind TCF/LEF, or the C-terminus, which is required for β-catenin binding, fail to antagonize Wnt signaling [47,48]. It will be of interest to investigate if this negative feedback loop exerted by Sox17 on Wnt signaling also occurs in endothelial cells.
Endothelial differentiation requires a well orchestrated effort of many families of transcription factors and the activation of several signaling pathways to create a functional vascular network of arteries, veins and lymphatics. Many groups have studied the contribution of Wnt or Notch signaling in the context of vascular development. Even if this approach has been informative, it could be restrictive as in a developing organism endothelial cells are exposed to different stimuli that result in the concomitant activation of more than just one signaling pathway. For instance, activation of Wnt pathway in endothelial cells drives arterial specification through Sox17 that, in turn, upregulates members of the Notch signaling pathway (Fig. 1). Furthermore, while data on the mechanisms that direct vascular differentiation are available, we know less on the factors that maintain arterio/venous identity. This is of high relevance as the lack of correct vascular differentiation may participate in the development of important disorders such as aneurysms, hemangiomas or altered revascularization of ischemic organs.
This work was supported by grants from: Associazione Italiana per la Ricerca sul Cancro (AIRC) and ‘Special Program Molecular Clinical Oncology 5x1000’ to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative), the European Research Council, the European Community (ITN VESSEL 317250, ENDOSTEM-HEALTH-2009-241440 and JUSTBRAIN-HEALTH-2009-241861), CARIPLO Foundation 2008.2463.
Conflicts of interest
There are no conflicts of interest.
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angiogenesis; endothelial cells; Notch; Sox; Wnt
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