Role of integrins in mouse eyelid development: studies in normal embryos and embryos in which there is a failure of eyelid fusion

Eyelid fusion normally occurs between E15.5 and E16.5 of mouse embryonic development and results from the migration of a population of periderm-derived epithelial cells over the corneal surface. Cell migration is known to depend on extracellular matrix receptors of the integrin family and to be regulated by growth factors. We were therefore interested thar a failure of eyelid fusion has been reported in mice that are homozygous null for the transforming growth factor alpha (TCF-alpha) gene and in mice (inv alpha(5)beta(1)) in which a transgenic alpha(5)beta(1) integrin under the control of the involucrin promoter is misexpressed in differentiating keratinocytes. We examined expression of the alpha(2)beta(1), alpha(3)beta(1), alpha(5)beta(1) and alpha(6)beta(4) integrins during eyelid fusion in wild-type embryos and found selective upregulation of the alpha(5)beta(1) integrin and its ligand, fibronectin, in the migrating eyelid tip cells. In TGF-alpha null embryos, the failure of eyelid fusion was correlated with a failure to upregulate the alpha(5)beta(1), integrin and fibronectin in the tip cells. Using beta-galactosidase as a reporter gene in transgenic mice, we observed specific activity of the involucrin promoter in the eyelid tip cells. In inv alpha(5)beta(1) mice the transgenic human integrin was overexpressed not only in the tip cells but throughout the eyelid epidermis. In contrast, the endogenous, murine. alpha(5)beta(1) integrin was only weakly expressed in the tip cells. We speculate that selective and coordinated expression of the alpha(5)beta(1) integrin and fibronectin in eyelid tip cells is required for eyelid fusion and may be under the control of growth factors that include TGF-alpha. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.