在組織受傷之後，其動態平衡受到干擾。皮膚間葉質向受傷的表皮細胞發出信號並共同協調傷口再生。並非所有的表皮細胞皆有能力接收此信號，如果表皮細胞具有這份能力，傷口就能再生。Homeobox基因編碼之轉錄因子，已被公認其在哺乳類動物的發育中扮演重要角色。Muscle segment homeobox gene-2 (Msx2)及Sex determining region Y-box-2 (Sox2)為形態發生因子。Msx2會在毛囊細胞中表現並調節毛髮之形態發生，且在皮膚傷口復原過程中在表皮被感測到(Yeh 2009, Hughes Submitted)。而Sox2用以維持及重新建構分化細胞使之成為幹細胞(Takahashi et al., 2007)。成鼠皮膚上的Sox2表現在guard, auchene和awl三種形態毛髮的真皮乳頭中，但不出現在zigzag形態。Merkel細胞為皮膚上的體感覺受器，亦有Sox2表現(Driskell, 2009)。WIHN(傷口誘導毛囊新生)是研究組織再生的分析試驗。有趣地是，只有zigzag形態的毛髮(Sox2-)在WIHN中再生(Ito et al., 2007)且Merkel細胞(Sox2+)再生失敗。我們假設homeobox基因，Msx2與Sox2，在WIHN中扮演調整傷口復原及再生的角色。藉由研究homeobox基因在WIHN中的功能，希望能發現掌控傷口復原及再生機制的新穎關鍵

After wounding, tissue homeostasis is perturbed. The wound mesenchyme signals the wound epithelium to synergistically coordinate the regeneration of the wound. If the epithelial cells are competent to inducing signals, the wound can regenerate. Homeobox genes are transcription factors that have been recognized to play key roles in mammalian development. Muscle segment homeobox 2 (Msx2) and Sex determining region Y-box-2 (Sox2) can act as morphogens. Msx2 is expressed in hair follicle cells, regulates hair morphogenesis, and is induced in the epidermis during skin wound healing (Yeh et al., 2009) (Hughes Submitted). Sox2 is required to maintain and reprogram differentiated cells into stem cells (Takahashi et al., 2007). In adult mouse skin, Sox2 is expressed in the dermal papilla of guard, auchene and awl hair follicle typers, but not in zigzag. The Merkel cell is a somatic sensory receptor in the skin and also expresses Sox2 (Driskell et al., 2009). WIHN (Wound-Induced Hair Neogenesis) is an assay for tissue regeneration. Interestingly, only zigzag hairs (Sox2-) regenerate during WIHN (Ito et al., 2007), and Merkel cells (Sox2+) fail to regenerate in this assay. We hypothesize the homeobox genes Msx2 and Sox2 play a role during WIHN and can modulate wound healing and regeneration. By studying the functions of homeobox genes during WIHN we hope to discover novel keys governing the mechanism of wound repair and regeneration.
 

Bardot, E. S., Valdes, V. J., Zhang, J., Perdigoto, C. N., Nicolis, S., Hearn, S. A., Silva, J. M., & Ezhkova, E. (2013). Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells. EMBO J, 32(14), 1990-2000. doi: 10.1038/emboj.2013.110
Brugger, S. M., Merrill, A. E., Torres-Vazquez, J., Wu, N., Ting, M. C., Cho, J. Y., Dobias, S. L., Yi, S. E., Lyons, K., Bell, J. R., Arora, K., Warrior, R., & Maxson, R. (2004). A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and Drosophila embryos. Development, 131(20), 5153-5165. doi: 10.1242/dev.01390
Chi, W., Wu, E., & Morgan, B. A. (2013). Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline. Development, 140(8), 1676-1683. doi: 10.1242/dev.090662
Clavel, C., Grisanti, L., Zemla, R., Rezza, A., Barros, R., Sennett, R., Mazloom, A. R., Chung, C. Y., Cai, X., Cai, C. L., Pevny, L., Nicolis, S., Ma'ayan, A., & Rendl, M. (2012). Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors. Dev Cell, 23(5), 981-994. doi: 10.1016/j.devcel.2012.10.013
Driskell, R. R., Giangreco, A., Jensen, K. B., Mulder, K. W., & Watt, F. M. (2009). Sox2-positive dermal papilla cells specify hair follicle type in mammalian epidermis. Development, 136(16), 2815-2823. doi: 10.1242/dev.038620
Driskell, R. R., Juneja, V. R., Connelly, J. T., Kretzschmar, K., Tan, D. W., & Watt, F. M. (2012). Clonal growth of dermal papilla cells in hydrogels reveals intrinsic differences between Sox2-positive and -negative cells in vitro and in vivo. J Invest Dermatol, 132(4), 1084-1093. doi: 10.1038/jid.2011.428
Fang, L., Zhang, L., Wei, W., Jin, X., Wang, P., Tong, Y., Li, J., Du, J. X., & Wong, J. (2014). A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation. Mol Cell, 55(4), 537-551. doi: 10.1016/j.molcel.2014.06.018
Gurtner, G. C., Werner, S., Barrandon, Y., & Longaker, M. T. (2008). Wound repair and regeneration. Nature, 453(7193), 314-321.
Hussein, S. M., Duff, E. K., & Sirard, C. (2003). Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. J Biol Chem, 278(49), 48805-48814. doi: 10.1074/jbc.M305472200
Ichida, J. K., Blanchard, J., Lam, K., Son, E. Y., Chung, J. E., Egli, D., Loh, K. M., Carter, A. C., Di Giorgio, F. P., Koszka, K., Huangfu, D., Akutsu, H., Liu, D. R., Rubin, L. L., & Eggan, K. (2009). A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 5(5), 491-503. doi: 10.1016/j.stem.2009.09.012
Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., Millar, S. E., & Cotsarelis, G. (2007). Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature, 447(7142), 316-320. doi: 10.1038/nature05766
Kishimoto, J., Burgeson, R. E., & Morgan, B. A. (2000). Wnt signaling maintains the hair-inducing activity of the dermal papilla. Genes & development, 14(10), 1181-1185.
Laga, A. C., Lai, C. Y., Zhan, Q., Huang, S. J., Velazquez, E. F., Yang, Q., Hsu, M. Y., & Murphy, G. F. (2010). Expression of the embryonic stem cell transcription factor SOX2 in human skin: relevance to melanocyte and merkel cell biology. Am J Pathol, 176(2), 903-913. doi: 10.2353/ajpath.2010.090495
Larson, B. J., Longaker, M. T., & Lorenz, H. P. (2010). Scarless fetal wound healing: a basic science review. Plast Reconstr Surg, 126(4), 1172-1180. doi: 10.1097/PRS.0b013e3181eae781
Levy, V., Lindon, C., Harfe, B. D., & Morgan, B. A. (2005). Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell, 9(6), 855-861. doi: 10.1016/j.devcel.2005.11.003
Ma, L., Liu, J., Wu, T., Plikus, M., Jiang, T. X., Bi, Q., Liu, Y. H., Muller-Rover, S., Peters, H., Sundberg, J. P., Maxson, R., Maas, R. L., & Chuong, C. M. (2003). 'Cyclic alopecia' in Msx2 mutants: defects in hair cycling and hair shaft differentiation. Development, 130(2), 379-389. doi: 10.1242/dev.00201
Morrison, J. I., Loof, S., He, P., & Simon, A. (2006). Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population. J Cell Biol, 172(3), 433-440. doi: 10.1083/jcb.200509011
Nelson, A. M., Reddy, S. K., Ratliff, T. S., Hossain, M. Z., Katseff, A. S., Zhu, A. S., Chang, E., Resnik, S. R., Page, C., Kim, D., Whittam, A. J., Miller, L. S., & Garza, L. A. (2015). dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration. Cell Stem Cell, 17(2), 139-151. doi: 10.1016/j.stem.2015.07.008
Perdigoto, C. N., Bardot, E. S., Valdes, V. J., Santoriello, F. J., & Ezhkova, E. (2014). Embryonic maturation of epidermal Merkel cells is controlled by a redundant transcription factor network. Development, 141(24), 4690-4696. doi: 10.1242/dev.112169
Shimizu, H., & Morgan, B. A. (2004). Wnt signaling through the β-catenin pathway is sufficient to maintain, but not restore, anagen-phase characteristics of dermal papilla cells. Journal of investigative dermatology, 122(2), 239-245.
Stelnicki, E. J., Kömüves, L. G., Holmes, D., Clavin, W., Harrison, M. R., Adzick, N. S., & Largman, C. (1997). The human homeobox genes MSX‐1, MSX‐2, and MOX‐1 are differentially expressed in the dermis and epidermis in fetal and adult skin. Differentiation, 62(1), 33-41.
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. cell, 131(5), 861-872.
Wang, J., Zhang, Y., Hou, J., Qian, X., Zhang, H., Zhang, Z., Li, M., Wang, R., Liao, K., Wang, Y., Li, Z., Zhong, D., Wan, P., Dong, L., Liu, F., Wang, X., Wan, Y., Xiao, W., & Zhang, W. W. (2016). Ube2s regulates Sox2 stability and mouse ES cell maintenance. Cell Death Differ, 23(3), 393-404. doi: 10.1038/cdd.2015.106
Yeh, J., Green, L. M., Jiang, T. X., Plikus, M., Huang, E., Chang, R. N., Hughes, M. W., Chuong, C. M., & Tuan, T. L. (2009). Accelerated closure of skin wounds in mice deficient in the homeobox gene Msx2. Wound Repair Regen, 17(5), 639-648. doi: 10.1111/j.1524-475X.2009.00535.x