Laminin-1 and receptors : Laminin α1 chain in important for epithelial development

Sammanfattning: Laminins are heterotrimeric glycoproteins that are major components of all basement membranes. Integrins from the β1 -famjly and the dystroglycan complex have been shown to be important receptors attaching epithelial cells to the underlying basement membrane. Several previous studies suggest that fragments E3 and E8 of laminin-1, binding to dystroglycan and integrin α6β1 respectively, are important for organogenesis in vitro. We have studied the function of the one chain of laminin-1 (the α1 chain) and the laminin-binding integrin subunit α6 during early mouse embryogenesis in vivo and in vitro. By gene targeting in embryonic stem cells a mouse model with a deletion of the laminin α1 E3 domain was obtained. Mice homozygous for the deletion died between the blastocyst stage and embryonic day 9.5, implicating an important function of this domain during early embryogenesis.By using a well characterized monoclonal antibody directed against the E3 domain of the laminin α1 chain, expression of the laminin a1 chain was studied. The expression pattern clearly demonstrated a restricted distribution of this chain, it was confined to some but not all epithelial cell basement membranes.The function of the integrin α6 integrins was studied in vitro using kidney organ culture and blocking antibodies. Kidney tubulogenesis in organ culture was severely perturbed in the presence of anti-integrin α6 antibodies. In embryonic kidneys the α6 subunit associated with β1, and not with the β4 chain. The cytoplasmic splice variant α6Β was the predominant form during tubulogenesis. These studies suggest a role for α6Ββ1 in kidney development, To be able to further study the role of the integrin α6 subunit, it was cloned in zebrafish and sequenced. Furthermore, the mRNA expression in embryos was studied. This is the first reponed intregrin receptor from this species.

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