β-Catenin-Dependent and -Independent Effects of ΔN-Plakoglobin on Epidermal Growth and Differentiation

Abstract

Both β-catenin and plakoglobin can stimulate the expression of Lef/Tcf target genes in vitro. β-Catenin is known to associate with Lef/Tcf factors and to participate directly in transactivation in vivo, whereas the role of plakoglobin in transcriptional regulation has been less studied. To analyze the functions of plakoglobin in vivo, we generated transgenic mice expressing in the epidermis N-terminally truncated plakoglobin (ΔN122-PG) lacking the glycogen synthase kinase 3β phosphorylation sites and therefore protected against degradation (transgenic line K5-ΔN122-PG). The expression of ΔN122-PG led to the formation of additional hair germs, hyperplastic hair follicles, and noninvasive hair follicle tumors, a phenotype reminiscent of that induced by expression of N-terminally truncated β-catenin. However, if expressed in β-catenin-null epidermis, ΔN122-PG did not induce new hair follicle germs and follicular tumors. Thus, ΔN122-PG cannot substitute for β-catenin in its signaling functions in vivo and the phenotype observed in K5-ΔN122-PG mouse skin must be due to the aberrant activation of β-catenin signaling. On the other hand, the expression of ΔN122-PG in β-catenin-null skin significantly increased the survival rate of mutant mice, rescued differentiation, and limited excessive proliferation in the interfollicular epidermis, suggesting that plakoglobin may be involved in the intracellular signaling events essential for epidermal differentiation.

We are grateful to Avri Ben-Ze'ev for encouraging us to study the signaling functions of plakoglobin in vivo and for advice on the manuscript. We particularly thank C. Goujet and the personnel of the Service d'Expérimentation Animale et de Transgenèse, Villejuif, especially R. Duchâteau and A. Loeuillet, for taking care of the transgenic mice. We also thank J. L. Jorcano for providing the K5 promoter construct and T. T. Sun and H. Clevers for donating reagents. We are grateful to F. Gaill and to M. J.-P. Lechaire for performing transmission electron microscopy and to M.-A. Deugnier and D. Medina for valuable discussions.

This work was supported by the Association pour la Recherche sur le Cancer (ARC 4440) and an ACI 2001 grant from the Ministère de la Recherche, France. J.T. is supported by a grant from the Association pour la Recherche sur le Cancer. M.M.F. is Chargé de Recherche, and M.A.G. is Directeur de Recherche at the Institut de la Santé et de la Recherche Médicale.