Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium

The Dkk family of secreted cysteine-rich proteins regulates Wnt/β-catenin signaling by interacting with the Wnt co-receptor Lrp5/6. Here, we show that Dkk2-mediated repression of the Wnt/β-catenin pathway is essential to promote differentiation of the corneal epithelial progenitor cells into a non-keratinizing stratified epithelium. Complete transformation of the corneal epithelium into a stratified epithelium that expresses epidermal-specific differentiation markers and develops appendages such as hair follicles is achieved in the absence of the Dkk2 gene function. We show that Dkk2 is a key regulator of the corneal versus epidermal fate of the ocular surface epithelium.

[1]  Steven J. M. Jones,et al.  A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. , 1999, Development.

[2]  F. Lovicu,et al.  Spatial and temporal expression of Wnt and Dickkopf genes during murine lens development. , 2004, Gene expression patterns : GEP.

[3]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

[4]  F. Watt Unexpected Hedgehog-Wnt interactions in epithelial differentiation. , 2004, Trends in molecular medicine.

[5]  C. Chuong,et al.  Shift of localized growth zones contributes to skin appendage morphogenesis: role of the Wnt/beta-catenin pathway. , 2003, The Journal of investigative dermatology.

[6]  W. Birchmeier,et al.  β-Catenin Controls Hair Follicle Morphogenesis and Stem Cell Differentiation in the Skin , 2001, Cell.

[7]  G. Pellegrini,et al.  Location and Clonal Analysis of Stem Cells and Their Differentiated Progeny in the Human Ocular Surface , 1999, The Journal of cell biology.

[8]  S. Tseng,et al.  Cytologic evidence of corneal diseases with limbal stem cell deficiency. , 1995, Ophthalmology.

[9]  Caiying Guo,et al.  Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation , 2005, Nature Genetics.

[10]  D. Dhouailly,et al.  Transdifferentiation of corneal epithelium into epidermis occurs by means of a multistep process triggered by dermal developmental signals. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[12]  P. Morin,et al.  β‐catenin signaling and cancer , 1999 .

[13]  E. Fuchs,et al.  Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. , 1999, Development.

[14]  J. Piatigorsky,et al.  Requirement for Pax6 in corneal morphogenesis: a role in adhesion , 2003, Journal of Cell Science.

[15]  D. Dhouailly,et al.  Adult corneal epithelium basal cells possess the capacity to activate epidermal, pilosebaceous and sweat gland genetic programs in response to embryonic dermal stimuli. , 2000, Development.

[16]  J. Nathans,et al.  A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Bouwmeester,et al.  The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals , 1999, Nature.

[18]  J. Nathans,et al.  A new secreted protein that binds to Wnt proteins and inhibits their activites , 1999, Nature.

[19]  R. Paus,et al.  Sonic hedgehog signaling is essential for hair development , 1998, Current Biology.

[20]  S. Tseng,et al.  Cytologlogic Evidence of Corneal Diseases with Limbal Stem Cell Deficiency , 1995 .

[21]  P. Morin,et al.  beta-catenin signaling and cancer. , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[22]  T. Hirano,et al.  Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation. , 2000, Developmental biology.

[23]  D. Dhouailly,et al.  Identification of keratins 3 and 12 in corneal epithelium of vertebrates. , 1993, Epithelial cell biology.

[24]  S. Millar,et al.  WNT signals are required for the initiation of hair follicle development. , 2002, Developmental cell.

[25]  Xi He,et al.  LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way , 2004, Development.

[26]  J. Wolosin,et al.  Ocular surface epithelial and stem cell development. , 2004, The International journal of developmental biology.

[27]  M. Kaufman,et al.  Corneal abnormalities in Pax6+/- small eye mice mimic human aniridia-related keratopathy. , 2003, Investigative ophthalmology & visual science.

[28]  E. Fuchs,et al.  Links between signal transduction, transcription and adhesion in epithelial bud development , 2003, Nature.

[29]  S. Millar WNTs: multiple genes, multiple functions. , 2003, The Journal of investigative dermatology.

[30]  Rainer Schmidt,et al.  The cornified envelope: a model of cell death in the skin , 2005, Nature Reviews Molecular Cell Biology.

[31]  F. Watt,et al.  Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. , 2005, Developmental cell.

[32]  J. I. Izpisúa Belmonte,et al.  Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. , 2001, Developmental cell.

[33]  T. Sun,et al.  Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: Implications on epithelial stem cells , 1989, Cell.

[34]  B. Hogan,et al.  Manipulating the mouse embryo: A laboratory manual , 1986 .

[35]  Andrew P McMahon,et al.  A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. , 2002, Development.

[36]  Hans Clevers,et al.  Notch1 functions as a tumor suppressor in mouse skin , 2003, Nature Genetics.

[37]  Christof Niehrs,et al.  Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. , 2003, Gene.