IN VIVO AND IN VITRO FUNCTIONAL STUDY OF TBX3, THE GENE MUTATED IN THE ULNAR MAMMARY SYNDROME

Several genetic diseases are caused by mutation in developmental genes: the development of specific body structures is affected from birth. In the "Ulnar-Mammary" disease one of the two copies of the TBX3 gene is inactive, while the other remains normal. These patients have malformation of the arms and a severe reduction of breast growth. We plan to understand how TBX3 regulates mammary cell growth using a combination of experimental methods, including a mouse model of the Ulnar-Mammary disease. In cultured mammary cells we plan to modify the expression of Tbx3 and observe their behavior (growth, formation of ducts, competence to produce milk proteins). Mammary cells with modified expression of Tbx3 will also serve the purpose of searching for "second order" genes that are directly influenced by the Tbx3 mutations. This search is essential for any future approach to design a therapy for the damaged breast tissue: the possibility to exploit the remaining normal copy of the TBX3 gene in Ulnar-Mammary patients and potentiate its own activity.In parallel we are generating a mouse model of the disease, in order to clarify the exact sequence of cell and tissue defects of the mammary gland. This will be done by a rigorous method (homologous recombination) that allows the introduction of a Tbx3 specific mutation only in the mammary tissue. With this model we will be able to observe the genesis of the mammary defect and characterize some of the molecular events.