Sox17 is indispensable for acquisition and maintenance of arterial identity

Corada, Monica; Orsenigo, Fabrizio; Morini, Marco; Pitulescu, Mara E.; Bhat, Ganesh; Nyqvist, Daniel; Breviario, Ferruccio; Conti, Valentina; Briot, Anaïs; Iruela‐Arispe, M. Luisa; Adams, Ralf H.; Dejana, Elisabetta

doi:10.1038/ncomms3609

Cited by 264 publications

(337 citation statements)

References 55 publications

Supporting

Mentioning

309

Contrasting

Unclassified

Order By: Relevance

“…We next examined the expression of two downstream Wnt/ β-catenin pathway target genes, Apcdd1 and sex determining region Y-box 17 (Sox17) (40,50), in spinal cords during EAE. In both vascular and nonvascular cells, expression of Apcdd1 mRNA was highly increased by EAE scores 1 and 3 using in situ hybridization with an antisense DIG-labeled probe ( .…”

Section: Resultsmentioning

confidence: 99%

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lengfeld

Lutz

Smith

et al. 2017

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

133

127

View full text Add to dashboard Cite

Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

show abstract

Section: Resultsmentioning

confidence: 99%

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lengfeld

Lutz

Smith

et al. 2017

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

133

127

View full text Add to dashboard Cite

show abstract

“…Several studies have demonstrated that SOX17 expression during endothelial differentiation is restricted to arteries (Corada et al, 2013;Frame et al, 2015;Matsui et al, 2006). By contrast, SOX7 is expressed from the onset of endothelial differentiation in the yolk sac at E7.5, and is expressed in arterial and venous vasculature (Gandillet et al, 2009;Sakamoto et al, 2007;Zhou et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the embryo proper, in the yolk sac HPCs emerge from a spectrum of endothelial cells in both arterial and venous regions, and in both large and small blood vessels (Frame et al, 2015). As the endothelial expression of SOX17 is restricted to arteries (Corada et al, 2013), this factor cannot control RUNX1 function and EHT in non-arterial vasculatures. Other endothelial transcription factors must therefore be important for regulating HE in the yolk sac.…”

Section: Introductionmentioning

confidence: 99%

“…SOX7 and RUNX1 are co-expressed in HE of the yolk sac and dorsal aorta Previous studies have suggested that SOX7 is expressed from the onset of endothelial differentiation in the yolk sac at E7.5, whereas SOX17 is expressed in developing arterial endothelium at later stages of development (Corada et al, 2013;Gandillet et al, 2009;Sakamoto et al, 2007). In order to define the expression of the three SOXF factors in yolk sac HE, we sorted FLK1 + /RUNX-RFP…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interplay between SOX7 and RUNX1 regulates hemogenic endothelial fate in the yolk sac

et al. 2016

View full text Add to dashboard Cite

Endothelial to hematopoietic transition (EHT) is a dynamic process involving the shutting down of endothelial gene expression and switching on of hematopoietic gene transcription. Although the factors regulating EHT in hemogenic endothelium (HE) of the dorsal aorta have been relatively well studied, the molecular regulation of yolk sac HE remains poorly understood. Here, we show that SOX7 inhibits the expression of RUNX1 target genes in HE, while having no effect on RUNX1 expression itself. We establish that SOX7 directly interacts with RUNX1 and inhibits its transcriptional activity. Through this interaction we demonstrate that SOX7 hinders RUNX1 DNA binding as well as the interaction between RUNX1 and its co-factor CBFβ. Finally, we show by single-cell expression profiling and immunofluorescence that SOX7 is broadly expressed across the RUNX1 + yolk sac HE population compared with SOX17. Collectively, these data demonstrate for the first time how direct protein-protein interactions between endothelial and hematopoietic transcription factors regulate contrasting transcriptional programs during HE differentiation and EHT.

show abstract

“…Sox18 is a member of the SoxF family of transcription factors that also includes Sox17 and Sox7 (Dunn et al, 1995). SoxF transcription factors have shown to modulate arteriovenous identity and lymphatic endothelial cell specification (Cermenati et al, 2008;Corada et al, 2013;Francois et al, 2008;Herpers et al, 2008;Pendeville et al, 2008). Previous studies have shown that adult Sox18-/-mice have a defect restricted to zigzag hairs supporting the view that Sox2 and Sox18 have complementing and nonoverlapping functions, driving the formation of different hair types (Pennisi et al, 2000a).…”

Section: Introductionmentioning

confidence: 87%

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Legrand¹

View full text Add to dashboard Cite

The hair follicle is an important skin appendage that arises during development from complex reciprocal signalling between the epidermis and dermis. The multiple epidermal layers of the hair follicle are known to be under the control of the mesenchymal component, the dermal papilla (DP), which has been described as the key regulator of hair follicle induction and maintenance. The hair follicle has elicited interest as a model system for the investigation of tissue and organ regeneration due to its ability to regenerate completely throughout the life of a mammal. This characteristic is attributed to the reservoir of stem cells within the hair follicle, which is modulated by the DP.Although it is known that the DP is central to regulation of the hair follicle, mediators of its signalling are incompletely understood. Potential mediators of DP activity continue to emerge, two of which include the SoxF transcription factor, Sox18, and the transcription factor, STAT5. Sox18 has been implicated in hair type specification by the DP; however, its expression and function remains unclear. STAT5 has been shown in microarray analyses of the DP to be specifically expressed and upregulated, while studies involving STAT5 genetic knockouts display a hair phenotype. More recently, STAT5 has been implicated in autoimmune conditions affecting the hair follicle such as alopecia areata.To investigate further the role of STAT5 in the DP, I have hypothesised that STAT5 plays a key role in the DP's hair follicle inductive properties and regulation of cycling.STAT5 activation in the DP was characterised through immunofluorescence staining of mouse back skin at various stages of hair follicle development and cycling. Back skin was obtained from Topflash transgenic mice, a canonical Wnt reporter transgenic mouse driving luciferase expression, using β-catenin activity to monitor hair cycling via live bioluminescence imaging. While embryonic skin did not display any activation of STAT5, during postnatal hair follicle development (P0-P19), the majority of phospho-STAT5 positive DP were present within telogen phase, to a lesser extent within catagen and not at all during anagen. Adult skin showed phospho-STAT5 activation beginning in late catagen and persisting through to early anagen.Characterisation of SOCS2 by immunofluorescence, a downstream STAT5 transcriptional target, showed expression corresponding to the chronology of phospho-STAT5 activity.Hair regeneration assays were performed with DP cells using SKP culture with STAT5 activity modified through adenovirus constructs. SKPs derived from C57BL/6 neonates and STAT5 lox/lox neonates were transduced with STAT5A/B constitutively-active and crerecombinase constructs, respectively. These transduced SKPs were then used in patch assay experiments and DP formation was quantified using a green fluorescent protein ii (GFP) reporter. SKPs transduced with constitutively-active STAT5 were significantly better at forming hair follicle DP than control SKPs transduced with GFP alone. SKPs with...

show abstract

Sox17 is indispensable for acquisition and maintenance of arterial identity

Cited by 264 publications

References 55 publications

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Interplay between SOX7 and RUNX1 regulates hemogenic endothelial fate in the yolk sac

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Contact Info

Product

Resources

About