Study on the in vivo interaction between integrins and fibronectin by knockin mice.

 Numerous in vitro and cell culture experiments have demostrated the important role of some fibronectin regions to bind integrins. Knockout-FN mice have early embryonic lethality, and exhibit several mesoderm defects. Also, the deletion of the major integrins that bind FN, such as α5 and α4, produce complex phenotypes with rather early embryonic lethality,making impossible to explain the specific role of fibronectin-integrins interactions during development.

In our lab, we are establishing different mice strains (knock-in) that express integrin-binding deficient FNs, and analyzing the functional consequences during development and the inmune system.

We are focus in the following specific mutant mice and interactions:

1. mice where the RGD motif (FNIII10) has been changed by RGE. This substitution abolishes the interaction between FN-RGD and α5β1 or αvβ3 integrins in vivo. The main phenotypic features of the mutant are: defectives angiogenesis and somitogenesis.
2. mice expressing a mutated variable region of FN (FN-IIICS). This modification abolishes FN binding to α4β1 and α4β7integrins. Haematopoiesis, angiogenesis and leukocyte extravasatian towards inflamation sites are the expected altered functions in these mice.
3. mice expressing a mutated synergy site (FNIII9) which cooperates in the interaction between the RGD domain and integrins. We expect defects related with the integrin activated function.

 Analysis of the role of Perlecan during brain development with knocout mice

Extracellulares matrices are networks that control cell proliferation and diferentiation. Among their components are the heparan sulfate proteoglycans, proteins that substituted by chains of sugars highly modified and bind diverse growth factors.

Our group has long experience in the study of the function of one of these proteoglycans, perlecan, which plays an important role in processes such as maintaining the basement membrane integrity, morphogenesis, angiogenesis , tumor metastasis and tissue repairing.