Elsevier

Matrix Biology

Volume 19, Issue 3, 1 July 2000, Pages 203-209
Matrix Biology

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In vivo functions of integrins: lessons from null mutations in mice

https://doi.org/10.1016/S0945-053X(00)00065-2Get rights and content

Abstract

The integrin family (Hynes, R.O., 1992. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69, 11–25) is composed of at least 24 heterodimers formed from eight β subunits and 18 α subunits. Thus far, mice expressing null mutations of seven of the eight β subunits and 13 of the 18 known α subunits have been generated, With only a few exceptions, the phenotypes of each of the knockout lines are quite distinct. Studies utilizing integrin knockout mice and cells derived from these mice have provided considerable and sometimes surprising insights into unique functions of individual members of this family.

Section snippets

β1 Subfamily

The largest subfamily of integrins is the group of 12 heterodimers that share the β1 subunit (Fig. 1). The critical roles played by β1 integrins in development are made clear by the phenotype produced by a homozygous null mutation of the β1 subunit gene (Fässler and Meyer, 1995, Stephens et al., 1995). This genotype results in very early embryonic lethality, with defects in gastrulation and death by day E5.5. The dramatic phenotype of β1 null homozygotes does not appear to result from an

αv Subfamily

At least five integrin heterodimers (αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8) contain the αv subunit (Fig. 2), and one additional integrin, αIIbβ3, is functionally closely related. All of these integrins recognize linear peptide epitopes in multiple ligands that include the tri-peptide arginine–glycine–aspartic acid (RGD). However, there are differences in ligand binding specificity among these integrins, with αvβ3 and αIIbβ3 each recognizing RGD in a wide array of contexts, and each of the other

β2 Subfamily

The β2 subfamily of integrins (Fig. 3) includes four members, αLβ2, αMβ2, αXβ2 and αDβ2. Thus far, null mutations have been described for β2 itself, inactivating the entire subfamily, and for αL and αM. The first attempt to inactivate the β2 subunit resulted in a hypomorphic allele rather than a true null (Wilson et al., 1993), but recently complete β2 null mice have been generated (Scharffetter-Kochanek et al., 1998). These mice have most of the features of the leukocyte adhesion deficiency

β7 Integrins

Because the β1 partner, α4, also forms a heterodimer with the β7 subunit, it is not formally possible to exclude some contribution of α4β7 to the effects of a null mutation of the α4 subunit gene. However, this issue has been largely addressed by the generation of mice expressing a null mutation in the β7 subunit (Wagner et al., 1996). These mice develop normally, but demonstrate an abnormality in the development of Peyer’s patches and a decrease in the number of intraepithelial lymphocytes,

Alternative splicing of integrin subunits

Several alternative splicing variants have been described in integrin subunits, especially in the short intracellular domains. For example, the structurally related α3, α6 and α7 subunits can each be formed with two alternative cytoplasmic domains, termed A and B, which are encoded by distinct alternatively spliced exons. The β1 subunit can be expressed with at least four alternate cytoplasmic domains, termed β1A, B, C and D. Thus far, informative mutations have been reported for alternatively

Summary

Over the past 8 years, nearly every integrin α and β subunit has been inactivated in mice. In a few cases the phenotypes of these mice recapitulated known human diseases (e.g. Leukocyte adhesion deficiency caused by inactivation of the β2 subunit and Glanzmann’s thrombasthenia caused by inactivation of the β3 subunit). However, contrary to the expectation of large degrees of overlap in in vivo function, most of these null mutations have resulted in dramatic and unique phenotypes. Initial

Acknowledgements

The author thanks Humphrey Gardner, Ambra Pozzi, and Paddy Ross for sharing results prior to publication and David Erle and Robert Pytela for helpful comments on the manuscript. Some of the work described in this review was supported by NIH grants HL/AI33259, HL47412, HL53949 and HL56385 (DS).

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