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Molecular and Cellular Biology, September 2006, p. 6609-6622, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00295-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mice with a Targeted Mutation of Patched2 Are Viable but Develop Alopecia and Epidermal Hyperplasia{dagger}

Erica Nieuwenhuis,1,2 Jun Motoyama,1,3 Paul C. Barnfield,1,2 Yoshiaki Yoshikawa,1,4 Xiaoyun Zhang,1 Rong Mo,1 Michael A. Crackower,1,2,5 and Chi-chung Hui1,2*

Program in Developmental Biology, The Hospital for Sick Children,1 Department of Molecular and Medical Genetics, University of Toronto, Toronto Medical Discovery Towers, 101 College Street, Toronto, Ontario M5G 1L7, Canada,2 Molecular Neuropathology Group, Brain Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan,3 Department of Dermatology, Tenri Hospital, 200 Michimo-cho, Tenri-shi, Nara 632-8552, Japan,4 Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Montreal, Quebec H3R 3P8, Canada5

Received 16 February 2006/ Returned for modification 15 April 2006/ Accepted 16 June 2006

Hedgehog (Hh) signaling plays pivotal roles in tissue patterning and development in Drosophila melanogaster and vertebrates. The Patched1 (Ptc1) gene, encoding the Hh receptor, is mutated in nevoid basal cell carcinoma syndrome, a human genetic disorder associated with developmental abnormalities and increased incidences of basal cell carcinoma (BCC) and medulloblastoma (MB). Ptc1 mutations also occur in sporadic forms of BCC and MB. Mutational studies with mice have verified that Ptc1 is a tumor suppressor. We previously identified a second mammalian Patched gene, Ptc2, and demonstrated its distinct expression pattern during embryogenesis, suggesting a unique role in development. Most notably, Ptc2 is expressed in an overlapping pattern with Shh in the epidermal compartment of developing hair follicles and is highly expressed in the developing limb bud, cerebellum, and testis. Here, we describe the generation and phenotypic analysis of Ptc2tm1/tm1 mice. Our molecular analysis suggests that Ptc2tm1 likely represents a hypomorphic allele. Despite the dynamic expression of Ptc2 during embryogenesis, Ptc2tm1/tm1 mice are viable, fertile, and apparently normal. Interestingly, adult Ptc2tm1/tm1 male animals develop skin lesions consisting of alopecia, ulceration, and epidermal hyperplasia. While functional compensation by Ptc1 might account for the lack of a strong mutant phenotype in Ptc2-deficient mice, our results suggest that normal Ptc2 function is required for adult skin homeostasis.

* Corresponding author. Mailing address: Program in Developmental Biology, The Hospital for Sick Children, Toronto Medical Discovery Towers, MaRS Building, East Tower, Room 13-314, Toronto, Ontario M5G 1L7, Canada. Phone: (416) 813-5681. Fax: (416) 813-5252. E-mail: cchui{at}sickkids.ca.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2006, p. 6609-6622, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00295-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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