EXPRESSION OF A TRUNCATED FGF RECEPTOR RESULTS IN DEFECTIVE LENS DEVELOPMENT IN TRANSGENIC MICE

Members of the fibroblast growth factor (FGF) family are thought to in itiate biological responses through the activation of cell surface rec eptors which must dimerize to transmit an intracellular signal. Mammal ian lens epithelial cells respond to exogenous extracellular FGF, eith er in tissue culture or in transgenic mice, by initiating fiber cell d ifferentiation. The role of FGF signalling in normal lens development was evaluated by lens-specific synthesis of a kinase-deficient FGF rec eptor type I (FGFR1) in transgenic mice. This truncated FGF receptor i s thought to act as a dominant negative protein by heterodimerization with endogenous FGF receptors. The presence of transgenic mRNA in the lens was confirmed by in situ hybridization and by polymerase chain re action amplification of reverse transcribed lens RNA (RT-PCR). The pre sence of transgenic protein was determined by Western blotting with an tibodies to an extracellular domain of FGFR1. Three of four transgenic families expressing the truncated FGF receptor exhibited lens defects ranging from cataracts to severe microphthalmia. While the microphtha lmic lenses displayed a normal pattern of differentiation-specific cry stallin expression, the lens epithelial cells were reduced in number a nd the lens fiber cells displayed characteristics consistent with the induction of apoptosis. Our results support the view that FGF receptor signalling plays an essential role in normal lens biology.