Research Interests

• Mouse developmental genetics
• Hedgehog signal transduction
• Skin development and cancer
• Neural patterning
• Stem cell development

Research Activities

Hedgehog signaling in development and disease

The Hedgehog signaling pathway plays a major role in the development of both invertebrates and vertebrates. In vertebrates, Hedgehog signaling controls embryonic patterning and the development of multiple organ systems. In humans, aberrations in the Hedgehog signaling pathway lead to congenital malformations and cancer. My laboratory is interested in understanding the molecular mechanisms underlying Hedgehog signal transduction in mammalian cells and how Hedgehog signaling affects both normal and abnormal developmental processes.

With biochemical and genetic studies, we have shown that three Gli transcription factors are involved in mammalian Hedgehog signal transduction. Through modulation of both activator and repressor functions of these transcription factors, Hedgehog signaling controls cell specification, differentiation, and proliferation. To investigate how the activity of these transcription factors are regulated, we have been studying the interactions of Gli proteins with several Hedgehog pathway components, including the Hedgehog receptors Ptc1 and Ptc2, and Suppressor of fused, and examining the role of these molecules in mammalian Hedgehog signaling.

Our developmental studies focus on the skin and nervous system because Hedgehog signaling is required for their normal development and abnormal activation of the Hedgehog pathway results in skin and brain tumours. Ongoing studies are directed to elucidate the cellular and molecular events that are involved in the normal and abnormal development of these organs.

External Funding

• National Cancer Institute of Canada (NCIC)
• Canadian Institutes of Health Research (CIHR)

Publications

Nieuwenhuis E, Barnfield PC, Makino S, Hui C-c. Epidermal hyperplasia and expansion of the interfollicular stem cell compartment in mutant mice with a C-terminal truncation of Patched1. Dev Biol 308, 547-560, 2007.

Lebel M, Mo R, Shimamura K, Hui C-c. Gli2 and Gli3 play distinct roles in the dorsoventral patterning of the mouse hindbrain. Dev Biol 302, 345-355, 2007.

Nieuwenhuis E, Motoyama J, Barnfield PC, Yoshikawa Y, Zhang X, Mo R, Crackower MA, Hui C-c. Mice with a targeted mutation of Patched2 are viable but develop alopecia and epidermal hyperplasia. Mol Cell Biol 26, 6609-6622, 2006.

Hu MC, Mo R, Bhella S, Wilson CW, Chuang P-T, Hui C-c, Rosenblum ND. GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development 133, 569-578, 2006.

Cheng CW, Yan CHM, Strahle U, Hui C-c, Cheng SH. The homeobox gene irx1a is required for the propagation of the neurogenic waves in the zebrafish retina. Mechanisms of Development 123, 252-263, 2006.

Cheng CW, Chow RL, Lebel M, Sakuma R, Cheung HO-L, Thanabalasingham V, Zhang X, Bruneau BG, Birch DG, Hui C-c, McInnes RR, Cheng SH. The Iroquois homeobox gene, Irx5, is required for retinal cone bipolar cell development. Dev Biol 287, 48-60, 2005.

Costantini DL, Arruda EP, Agarwal P, Kim K-H, Zhu Y, Zhu W, Lebel M, Cheng CW, Park CY, Pierce SA, Guerchicoff A, Pollevick GD, Chan TY, Kabir G, Cheng SH, Husain M, Antzelevitch C, Srivastava D, Gross GJ, Hui C-c, Backx PH, Bruneau B. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Cell 123, 347-358, 2005.

Mill P, Mo R, Hu MC, Dagnino L, Rosenblum ND, Hui C-c. Shh controls epithelial proliferation via independent pathways that converge on N-Myc. Dev Cell 9, 293-303, 2005.

Motoyama J, Milenkovic L, Iwana M, Shikata Y, Scott MP, Hui C-c. Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev Biol 259, 150-161, 2003.

Buttitta L, Mo R, Hui C-c, Fan C-M. Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome development. Development 130, 6233-6243, 2003.

Mill P, Mo R, Fu H, Grachtchouk M, Kim P, DlugoszA, Hui C-c. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev 17, 282-294, 2003.

Taylor MD, Liu L, Raffel C, Hui C-c, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma. Nature Genetics 31, 306-310, 2002.

Meng X, Poon R, Zhang X, Cheah A, Ding Q, Hui C-c, Alman B. Suppressor of fused negatively regulates b-catenin signaling. J Biol Chem 276, 40113-40119, 2001.

Kim J, Kim PCW, Hui C-c. The VACTERL association: lessons form the Shh signaling pathway. Clin Genet 59: 306-315, 2001.

Cohen DR, Cheng CW, Cheng SH, Hui C-c. Expression of two novel Iroquois homeobox genes during neurogenesis. Mechanisms of Development 91, 317-321, 2000.

Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui C-c, Dlugosz AA. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genetics 24, 216-217, 2000.

Ding Q, Fukami S-I, Meng X, Nishizaki Y, Zhang X, Sasaki H, Dlugosz A, Nakafuku M, Hui C-c. Mouse Suppressor of fused is a negative regulator of Shh signaling and alters the subcellular distribution of Gli1. Current Biology 9, 1119-1122, 1999.

Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui C-c. Essential functions of Gli2 and Gli3 zinc finger genes in the formation of lung, trachea and esophagus. Nature Genetics 20, 54-57, 1998.

Ding Q, Motoyama J, Gasca S, Mo R, Sasaki H, Rossant J, Hui C-c. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 125, 2533-2543, 1998.

Motoyama J, Takabatake T, Takeshima K, Hui C-c. Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog. Nature Genetics 18, 104-106, 1998.

Motoyama J, Heng H, Crackower MA, Takabatake T, Takeshima K, Tsui L-C, Hui C. Overlapping and non-overlapping Ptch2 expression with Shh during mouse embryogenesis. Mechanisms of Development, 78: 81-84, 1998.

Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH, Joyner AL, Hui C. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development, 124: 113-123, 1997.

Intellectual Property

• Transgenic mouse model of basal cell carcinoma