[Spatio-temporal control of oncogenesis].

Experimental carcinogenesis has, until recently, relied on the use of animal models in which the tumorigenic process is distantly related to that observed in humans. More recently the use of transgenic mice has open new opportunities but has also revealed two limitations: firstly, some of the most prominent tumors observed in genetically predisposed humans are not observed in the corresponding mice; secondly, in most instances mice carrying a totally inactivated tumor suppressor gene die early during development. To overcome these difficulties we have developed a modular transgenic mouse model for the tissue-specific inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene. Mutations are induced by breeding mice carrying different combinations of null and targeted but functional alleles. The regulated induction of tissue-specific somatic lesions is achieved by in vivo activation of site-specific recombination with Cre recombinase that mediate excision of sequences at specific recognition sites (loxP). In this conditional knock-out model, an additional degree of sophistication enables to trigger the creation of defined somatic mutations not only in a tissue-specific manner but also at a time that is decided by the investigator. This approach is made possible by the development of inducible regulatory systems. This further development should provide excellent flexibility to analyse in detail the consequences of the occurrence in time of the different mutations that contribute to tumor initiation and progression.