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

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. Summary: The Sox18Op/+ mutation in mice, which mimics a hair loss condition in humans, leads to decreasing Wnt signal interactions with the hair follicle epidermis and abnormal hair follicle morphology.

[1]  J. Schittny,et al.  Tenascin-C is required for normal Wnt/β-catenin signaling in the whisker follicle stem cell niche. , 2014, Matrix biology : journal of the International Society for Matrix Biology.

[2]  K. Khosrotehrani,et al.  Transgenic flash mice for in vivo quantitative monitoring of canonical Wnt signaling to track hair follicle cycle dynamics. , 2014, The Journal of investigative dermatology.

[3]  S. Stacker,et al.  Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development. , 2014, Human molecular genetics.

[4]  M. Corada,et al.  Sox17 is indispensable for acquisition and maintenance of arterial identity , 2013, Nature Communications.

[5]  F. Watt,et al.  Sox2 modulates the function of two distinct cell lineages in mouse skin☆ , 2013, Developmental biology.

[6]  K. Khosrotehrani,et al.  Reduced Il17a expression distinguishes a Ly6c(lo)MHCII(hi) macrophage population promoting wound healing. , 2013, The Journal of investigative dermatology.

[7]  S. Aerts,et al.  Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation , 2012, Nature Cell Biology.

[8]  Avi Ma'ayan,et al.  Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors. , 2012, Developmental cell.

[9]  H. Zhen,et al.  Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop. , 2012, Genes & development.

[10]  O. Wagner,et al.  The Transcription Factor SOX18 Regulates the Expression of Matrix Metalloproteinase 7 and Guidance Molecules in Human Endothelial Cells , 2012, PloS one.

[11]  Maria I Morasso,et al.  Epidermal patterning and induction of different hair types during mouse embryonic development. , 2009, Birth defects research. Part C, Embryo today : reviews.

[12]  F. Watt,et al.  Sox2-positive dermal papilla cells specify hair follicle type in mammalian epidermis , 2009, Development.

[13]  F. Orsenigo,et al.  Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice , 2009, Development.

[14]  F. Orsenigo,et al.  Sox 7 and Sox 17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox 18 dysfunction in mice , 2009 .

[15]  F. Orsenigo,et al.  Sox18 induces development of the lymphatic vasculature in mice , 2008, Nature.

[16]  J. Martial,et al.  Zebrafish Sox7 and Sox18 function together to control arterial-venous identity. , 2008, Developmental biology.

[17]  Jamie A Davies,et al.  GUDMAP: the genitourinary developmental molecular anatomy project. , 2008, Journal of the American Society of Nephrology : JASN.

[18]  E. Dejana,et al.  Sox18 and Sox7 play redundant roles in vascular development. , 2008, Blood.

[19]  E. V. D. van de Kamp,et al.  Redundant Roles for Sox7 and Sox18 in Arteriovenous Specification in Zebrafish , 2008, Circulation research.

[20]  F. Miller,et al.  Skin-Derived Precursors Generate Myelinating Schwann Cells That Promote Remyelination and Functional Recovery after Contusion Spinal Cord Injury , 2007, The Journal of Neuroscience.

[21]  J. Ortonne,et al.  Sox9 Is Essential for Outer Root Sheath Differentiation and the Formation of the Hair Stem Cell Compartment , 2005, Current Biology.

[22]  L. Pevny,et al.  SOX2 Functions to Maintain Neural Progenitor Identity , 2003, Neuron.

[23]  K. Devriendt,et al.  Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. , 2003, American journal of human genetics.

[24]  P. Koopman,et al.  Sox18 mutations in the ragged mouse alleles ragged‐like and opossum , 2003, Genesis.

[25]  S. Millar,et al.  Molecular mechanisms regulating hair follicle development. , 2002, The Journal of investigative dermatology.

[26]  Sarah E. Millar,et al.  Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis , 2001, Mechanisms of Development.

[27]  A. Nagy,et al.  Mice Null for Sox18 Are Viable and Display a Mild Coat Defect , 2000, Molecular and Cellular Biology.

[28]  C. Abbott,et al.  Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice , 2000, Nature Genetics.

[29]  R Paus,et al.  A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. , 1999, The Journal of investigative dermatology.

[30]  G. Muscat,et al.  Sequence and expression of Sox-18 encoding a new HMG-box transcription factor. , 1995, Gene.

[31]  K. Holbrook,et al.  Dynamic expression patterns of tenascin, proteoglycans, and cell adhesion molecules during human hair follicle morphogenesis , 1994, Developmental dynamics : an official publication of the American Association of Anatomists.

[32]  J. Slee.  Developmental morphology of the skin and hair follicles in normal and in 'ragged' mice. , 1962, Journal of embryology and experimental morphology.

[33]  T. Carter,et al.  RAGGED, A SEMIDOMINANT COAT TEXTURE MUTANT In the House Mouse , 1954 .