J. Cell Biol., Volume 143, Number 1, October 5, 1998 253-266

Cre-loxP-mediated Inactivation of the 6A Integrin Splice Variant In Vivo: Evidence for a Specific Functional Role of 6A in Lymphocyte Migration but Not in Heart Development

Clotilde Gimond, Christian Baudoin, Ronald van der Neut, Duco Kramer, Jero Calafat, and Arnoud Sonnenberg

Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Two splice variants of the 6 integrin subunit, 6A and 6B, with different cytoplasmic domains, have previously been described. While 6B is expressed throughout the development of the mouse, the expression of 6A begins at 8.5 days post coitum and is initially restricted to the myocardium. Later in ontogeny, 6A is found in various epithelia and in certain cells of the immune system. In this study, we have investigated the function of 6A in vivo by generating knockout mice deficient for this splice variant. The Cre- loxP system of the bacteriophage P1 was used to specifically remove the exon encoding the cytoplasmic domain of 6A in embryonic stem cells, and the deletion resulted in the expression of 6B in all tissues that normally express 6A. We show that 6A/ mice develop normally and are fertile. The substitution of 6A by 6B does not impair the development and function of the heart, hemidesmosome formation in the epidermis, or keratinocyte migration. Furthermore, T cells differentiated normally in 6A/ mice. However, the substitution of 6A by 6B leads to a decrease in the migration of lymphocytes through laminin-coated Transwell filters and to a reduction of the number of T cells isolated from the peripheral and mesenteric lymph nodes. Lymphocyte homing to the lymph nodes, which involves various types of integrin-ligand interactions, was not affected in the 6A knockout mice, indicating that the reduced number of lymph node cells could not be directly attributed to defects in lymphocyte trafficking. Nevertheless, the expression of 6A might be necessary for optimal lymphocyte migration on laminin in certain pathological conditions.

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