Developmental Genetics of Planar Cell Polarity in Mammalian Skin
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. Using mouse skin as a model system, we are interested in dissecting the mechanisms of mammalian PCP and helping us better understand the development of PCP-related diseases.
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 (Fz6-/-) mutant mice, hair follicles develop normally with respect to their intrinsic structure, but they exhibit random orientations relative to the body axis (Fig. 1). By a series of mosaic deletion experiments, we demonstrated that Fz6-induced PCP signaling acts mainly to locally communicate polarity information, but not for transmitting polarity information over long distances. Ongoing research is to identify downstream effectors and binding partners of Fz6 during hair follicle patterning in skin.
Fig. 1 Hair follicles on the back of wild-type or Fz6-/- mice at postnatal day 3, visualized based on melanin pigmentation
Astrotactin2 in PCP and development
Through forward genetic studies with naturally occurred ridge mice, we identified a novel PCP modifier gene that controls hair orientation – Astrotactin2 (Astn2). Loss of Astn2 exon 5 creates an initial posterior-to-anterior hair follicle orientation bias in the back skin of Fz6 mutant mice, resulting in a transverse ridge across the back in adults (Fig. 2). Astn2 is highly expressed in skin, brain, testis and liver by RNA in situ hybridization. Ongoing research is to determine the role of Astn2 in PCP and development using an Astn2 conditional knockout mouse line that we recently generated.
Fig. 2 An unusual hairdo in mice: a transverse ridge across the back of Fz6-/- mice
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- Chang, H. (2017) Cleave but not leave: Astrotactin proteins in development and disease. IUBMB Life. 69:572-577.
- Chang, H., Smallwood, P.M., Williams, J., Nathans, J. (2017) Intramembrane Proteolysis of Astrotactins. Journal of Biological Chemistry. 292:3506-3516.
- Wang, Y., Chang, H., Rattner, A., Nathans, J. (2016) Frizzled receptors in development and disease. Current Topics in Developmental Biology. 117:113-139.
- Chang, H., Smallwood, P.M., Williams, J., Nathans, J. (2016) The spatio-temporal domains of Frizzled6 action in planar polarity control of hair follicle orientation. Developmental Biology. 409:181-193.
- Chang, H., Cahill, H., Smallwood, P.M., Wang, Y., Nathans, J. (2015) Identification of Astrotactin2 as a genetic modifier that regulates the global orientation of mammalian hair follicles. PLOS Genetics. 11: e1005532.
- Hua, Z.L.*, Chang, H.*, Wang, Y., Smallwood, P.M., Nathans, J. (2014) Partial interchangeability of Fz3 and Fz6 in tissue polarity signaling for epithelial orientation and axon growth and guidance. Development. 141:3944-3954. *equal contribution.
- Chang, H.#, Wang, Y., Wu, H., Nathans, J. # (2014) Flat mount imaging of mouse skin and its application to the analysis of hair follicle patterning and sensory axon morphology. Journal of Visualized Experiments. 88:e51749. #co-corresponding authors.
- Chang, H., Nathans, J. (2013) Responses of hair follicle-associated structures to loss of planar cell polarity signaling. Proceedings of the National Academy of Sciences USA. 110:E908-917.
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