Integrin function and regulation in development

Integrins are a large family of membrane receptors, consisting of alpha and beta subunits, that play a pivotal role in the interaction of cells with t he extracellular matrix. Such interaction regulates the organization of cel ls in organs and tissues during development as well as cell differentiation and proliferation. We have shown that unfertilized oocytes express integri ns that might be important during fertilization. We also analyzed nervous s ystem and muscle tissue development showing that integrin expression is pre cisely regulated during organization of these tissues. The results indicate that two distinct integrin alpha subunits mediate the outgrowth of process es in nerve and glial cells. alpha1 integrin, a laminin receptor, is up-reg ulated by nerve growth factor and other differentiation stimuli and is invo lved in neurite extension by nerve cells. In contrast, process extension by glial cells is likely to involve the alphaV integrin. Moreover, the latter integrin subunit is also transiently expressed in muscle of the embryo bod y where it localizes predominantly at developing myotendinous junctions. Af ter birth this integrin disappears and is substituted by the alpha7 subunit . At the same time, important changes also occur in the expression of the a ssociated beta subunit. In fact, the beta 1A isoform which is expressed in fetal muscles, is substituted by beta 1D. These isoforms are generated by a lternative splicing and differ in only a few amino acid residues at the COO H terminus of the protein. This region of the molecule is exposed at the cy toplasmic face of the plasma membrane and is connected to the actin filamen ts. Our results show that beta 1D which is expressed only in striated muscl e tissues, binds to both cytoskeletal and extracellular matrix proteins wit h an affinity higher than beta 1A. Thus, beta 1D provides a stronger link b etween the cytoskeleton and extracellular matrix necessary to support mecha nical tension during muscle contraction. These results indicate that cells can regulate their interactions with the extracellular matrix by changing t heir expression of a integrin subunits and thus ligand specificity, or by m ore subtle changes involving alternative usage of different cytoplasmic dom ains. The important role of both alpha and beta integrin subunit cytoplasmi c domains during development is further illustrated by the analysis of targ eted mutations which we have generated by homologous recombination in mice.