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

doi:10.1083/jcb.143.1.253

A correction to this article has been published: J. Cell Biol. 143 (5) 1413

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© The Rockefeller University Press, 0021-9525/1998//253 $5.00
The Journal of Cell Biology, Volume 143, Number 1, , 1998 253-266

Regular Articles

Cre-loxP–mediated Inactivation of the ${alpha}$ 6A Integrin Splice Variant In Vivo: Evidence for a Specific Functional Role of ${alpha}$ 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 ${alpha}$ 6 integrin subunit, ${alpha}$ 6A and ${alpha}$ 6B, withdifferent cytoplasmic domains, have previously been described.While ${alpha}$ 6B is expressed throughout the development of the mouse,the expression of ${alpha}$ 6A begins at 8.5 days post coitum and is initially restricted to the myocardium. Later in ontogeny, ${alpha}$ 6A is found in various epithelia and in certain cells of theimmune system. In this study, we have investigated the functionof ${alpha}$ 6A in vivo by generating knockout mice deficient for thissplice variant. The Cre- loxP system of the bacteriophage P1was used to specifically remove the exon encoding the cytoplasmicdomain of ${alpha}$ 6A in embryonic stem cells, and the deletion resultedin the expression of ${alpha}$ 6B in all tissues that normally express ${alpha}$ 6A. We show that ${alpha}$ 6A–/– mice develop normally andare fertile. The substitution of ${alpha}$ 6A by ${alpha}$ 6B does not impair thedevelopment and function of the heart, hemidesmosome formationin the epidermis, or keratinocyte migration. Furthermore, Tcells differentiated normally in ${alpha}$ 6A–/– mice. However,the substitution of ${alpha}$ 6A by ${alpha}$ 6B leads to a decrease in the migrationof lymphocytes through laminin-coated Transwell filters andto a reduction of the number of T cells isolated from the peripheraland mesenteric lymph nodes. Lymphocyte homing to the lymphnodes, which involves various types of integrin–ligandinteractions, was not affected in the ${alpha}$ 6A knockout mice, indicating that the reduced number of lymph node cells could not be directlyattributed to defects in lymphocyte trafficking. Nevertheless,the expression of ${alpha}$ 6A might be necessary for optimal lymphocytemigration on laminin in certain pathological conditions.

Key Words: integrin • laminin receptor • knockout • migration • lymphocyte

Abbreviations used in this paper: dpc, days post coitum; ES, embryonic stem.

All of the ES cell work was carried out in the division of MolecularGenetics (Head Prof. Dr. A. Berns) at the Netherlands CancerInstitute. This work was supported by a fellowship from theEuropean Commission (ERB4050PL930847) to C. Gimond, a MarieCurie Research training grant from the European Commission(ERBFMBICT961823) to C. Baudoin, and grants from the NetherlandsHeart Foundation (NHS 96.006) and the Netherlands Organizationfor Scientific Research (NWO 900-511-043).

Address all correspondence to Arnoud Sonnenberg, Division ofCell Biology, The Netherlands Cancer Institute, Plesmanlaan121, 1066 CX Amsterdam, The Netherlands. Tel.: (31) 20 512 1942.Fax: (31) 20 512 1944. E-mail: asonn{at}nki.nl

Ronald van der Neut's present address is INSERM U434, 27 rueJuliette Dodu, 75010 Paris, France.

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