Arap3 is dysregulated in a mouse model of hypotrichosis–lymphedema–telangiectasia and regulates lymphatic vascular development

Kartopawiro, Joëlle; Bower, Neil I.; Karnezis, Tara; Kazenwadel, Jan; Betterman, Kelly L.; Lesieur, Emmanuelle; Koltowska, Katarzyna; Astin, Jonathan W.; Crosier, Philip S.; Vermeren, Sonja; Achen, Marc G.; Stacker, Steven A.; Smith, K. A.; Harvey, Natasha L.; François, Mathias; Hogan, Benjamin M.

doi:10.1093/hmg/ddt518

Cited by 35 publications

(44 citation statements)

References 56 publications

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“…We performed a comprehensive analysis of Sox18 expression pattern, as determined by the activity of its endogenous regulatory elements during skin embryonic development (from E14.5 to E18.5) using a Sox18-GFP/CreER (Sox18 +/GFPCre ) knock-in reporter mouse, which expresses GFP under the control of the endogenous Sox18 promoter (Kartopawiro et al, 2014;McMahon et al, 2008). In the skin, expression of Sox18, as revealed by GFP detection, was restricted at all time-points to the DC structures, apart from some expected remnant expression in vascular structures.…”

Section: Sox18 Is Expressed In the Dermal Papilla Of All Hfs During Dmentioning

confidence: 99%

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Dominant-negative Sox18 function inhibits dermal papilla maturation and differentiation in all murine hair types

et al. 2017

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SOX family proteins SOX2 and SOX18 have been reported as being essential in determining hair follicle type; however, the role they play during development remains unclear. Here, we demonstrate that Sox18 regulates the normal differentiation of the dermal papilla of all hair types. In guard ( primary) hair dermal condensate (DC) cells, we identified transient Sox18 in addition to SOX2 expression at E14.5, which allowed fate tracing of primary DC cells until birth. Similarly, expression of Sox18 was detected in the DC cells of secondary hairs at E16.5 and in tertiary hair at E18.5. Dominant-negative Sox18 mutation (opposum) did not prevent DC formation in any hair type. However, it affected dermal papilla differentiation, restricting hair formation especially in secondary and tertiary hairs. This Sox18 mutation also prevented neonatal dermal cells or dermal papilla spheres from inducing hair in regeneration assays. Microarray expression studies identified WNT5A and TNC as potential downstream effectors of SOX18 that are important for epidermal WNT signalling. In conclusion, SOX18 acts as a mesenchymal molecular switch necessary for the formation and function of the dermal papilla in all hair types.

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Section: Sox18 Is Expressed In the Dermal Papilla Of All Hfs During Dmentioning

confidence: 99%

“…+/Sox18GCre mice were kindly provided by Dr Andy McMahon (Kartopawiro et al, 2014;McMahon et al, 2008). Sox18 +/Op mice were obtained from Prof. Peter Koopman (Institute for Molecular Bioscience, The University of Queensland, Australia) and +/Flash reporter mice were as described previously (Hodgson et al, 2014).…”

Section: Mouse Modelsmentioning

confidence: 99%

Dominant-negative Sox18 function inhibits dermal papilla maturation and differentiation in all murine hair types

et al. 2017

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“…The ARAPs control trafficking of a number of transmembrane receptors including a 5 b 1 integrin and EGFR and affect cell adhesion, migration, insulin secretion and lymphatic vascular development. [64][65][66][67][68][69] ARAP3 has been reported to inhibit dissemination of scirrhous gastric cancer. 70 AGAPs are composed of a G-protein like, PH, Arf GAP and Ank repeat domains.…”

Section: Introductionmentioning

confidence: 99%

Allosteric properties of PH domains in Arf regulatory proteins

et al. 2016

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Pleckstrin Homology (PH) domains bind phospholipids and proteins. They are critical regulatory elements of a number enzymes including guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) for Ras-superfamily guanine nucleotide binding proteins such as ADP-ribosylation factors (Arfs). Recent studies have indicated that many PH domains may bind more than one ligand cooperatively. Here we discuss the molecular basis of PH domain-dependent allosteric behavior of 2 ADPribosylation factor exchange factors, Grp1 and Brag2, cooperative binding of ligands to the PH domains of Grp1 and the Arf GTPase-activating protein, ASAP1, and the consequences for activity of the associated catalytic domains.

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“…Sox18GCre/ER mice were generated and kindly provided by Dr. Andrew McMahon (Kartopawiro et al, 2014;McMahon et al, 2008), Sox18 +/Op mice were obtained from Prof.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…Using Sox18GCre/ER reporter mice we performed a comprehensive analysis of Sox18 expression pattern as determined by the activity of its endogenous promoter during skin embryonic development (from E14.5 to E18.5) (Kartopawiro et al, 2014;McMahon et al, 2008). Expression of Sox18 at all timepoints was restricted to the DC with expectedly some remnant expression in vascular structures.…”

Section: Sox18 Is Expressed In the Dermal Papilla Of All Hair Folliclmentioning

confidence: 99%

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Legrand¹

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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...

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Arap3 is dysregulated in a mouse model of hypotrichosis–lymphedema–telangiectasia and regulates lymphatic vascular development

Cited by 35 publications

References 56 publications

Dominant-negative Sox18 function inhibits dermal papilla maturation and differentiation in all murine hair types

Dominant-negative Sox18 function inhibits dermal papilla maturation and differentiation in all murine hair types

Allosteric properties of PH domains in Arf regulatory proteins

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

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