1. ¹Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
2. ²Department of Otolaryngology, Oregon Health and Science University, Portland, OR, USA

Correspondence: Dr X-J Wang, Department of Otolaryngology, Oregon Health and Science University, Portland, OR 97239, USA E-mails: wangxiao@ohsu.edu or chuxiad@bdg10.niddk.nih.gov or chuxiad@mail.nih.gov; Dr C-X Deng, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bldg. 10 Rm. 9N105, Bethesda, MD 20892, USA.

Received 31 May 2005; Revised 19 July 2005; Accepted 19 July 2005; Published online 19 September 2005.

Abstract

Smad4 is the common mediator for TGF signals, which play important functions in many biological processes. To study the role of Smad4 in skin development and epidermal tumorigenesis, we disrupted this gene in skin using the Cre-loxP approach. We showed that absence of Smad4 blocked hair follicle differentiation and cycling, leading to a progressive hair loss of mutant (MT) mice. MT hair follicles exhibited diminished expression of Lef1, and increased proliferative cells in the outer root sheath. Additionally, the skin of MT mice exhibited increased proliferation of basal keratinocytes and epidermal hyperplasia. Furthermore, we provide evidence that the absence of Smad4 resulted in a block of both TGF and bone morphogenetic protein (BMP) signaling pathways, including p21, a well-known cyclin-dependent kinase inhibitor. Consequently, all MT mice developed spontaneous malignant skin tumors from 3 months to 13 months of age. The majority of tumors are malignant squamous cell carcinomas. A most notable finding is that tumorigenesis is accompanied by inactivation of phosphatase and tensin homolog deleted on chromosome 10 (Pten), activation of AKT, fast proliferation and nuclear accumulation of cyclin D1. These observations revealed the essential functions of Smad4-mediated signals in repressing skin tumor formation through the TGF/BMP pathway, which interacts with the Pten signaling pathway.