Ph.D., University of Texas Health Science Center at Houston
Address: MSC, Room 417
Planar cell polarity in mammalian skin development and cancer
Mouse Genetics; Developmental Biology; Cancer Genetics
Research in my lab focuses on understanding the developmental mechanisms that pattern cells in tissue planes and body axes, a phenomenon known as planar cell polarity (PCP). Mutations in PCP genes have been found to cause many diseases in human patients and/or in mouse models, such as neural tube closure defects, polycystic kidney disease, axon guidance defects and cleft palate. Elevated expression of PCP genes has also been found in various tumor cells, suggesting a role of PCP in tumorigenesis. Using mouse skin as a model system, we are interested in dissecting the mechanisms of mammalian PCP and facilitating the development of therapeutic interventions for PCP-related diseases, including cancer.
(1) Frizzled6 signaling in hair orientation control.
Mouse back skin has thousands of hair follicles. Each hair follicle grows uniformly in an anterior-to-posterior direction, parallel to the body axis. In Frizzled6 (Fzd6-/-) mutant mice, hair follicles develop normally with respect to their intrinsic structure, but they exhibit random orientations relative to the body axis. Using a series of mosaic deletion experiments, we demonstrated that Fzd6-induced PCP signaling acts mainly to locally communicate polarity information, but not for transmitting polarity information over long distances. Ongoing research will identify downstream effectors and binding partners of Fzd6 during hair follicle patterning in skin.
(2) PCP pathway in skin tumorigenesis.
We found elevated expression of PCP pathway genes in various tumor cell lines, including melanoma and epidermoid carcinoma cell lines. For example, expression of Astrotactin2 (Astn2) is upregulated in the malignant melanoma cell line; expression of Fzd3 and Fzd6 is upregulated in both the malignant melanoma cell line and the epidermoid carcinoma cell line. We have generated various genetically modified mice (e.g. conditional knockout mice for Fzd3, Fzd6 and Astn2 and conditional overexpressing mice for Fzd3 and Fzd6). By crossing the PCP mutant mouse lines that we have made to various genetic models of skin tumors, we will determine the in vivo function of PCP genes in skin tumor initiation, progression and metastasis.
Chang, H., Smallwood, P.S., Williams, J., Nathans, J. (2016) The spatio-temporal domains of Frizzled6 action in planar polarity control of hair follicle orientation. Dev Biol. 409: 181-193.
Chang, H., Cahill, H., Smallwood, P.S., Wang, Y., Nathans, J. (2015) Identification of Astrotactin2 as a genetic modifier that regulates the global orientation of mammalian hair follicles. PLOS Genet. 11: e1005532.
Chang, H., Nathans, J. (2013) Responses of hair follicle-associated structures to loss of planar cell polarity signaling. Proc Natl Acad Sci U S A. 110: E908-17.
Chang, H., Guillou, F., Taketo, M.M., Behringer, R.R. (2009) Overactive beta-catenin signaling causes testicular Sertoli cell tumor development in the mouse. Biology of Reproduction. 81:842-849.