EXTRACELLULAR FGF-1 ACTS AS A LENS DIFFERENTIATION FACTOR IN TRANSGENIC MICE

The vertebrate ocular lens undergoes a spatially defined pattern of di fferentiation which may be regulated by the ocular distribution of pro teins from the fibroblast growth factor (FGF) family. The ability of a ltered FGF-1 (acidic FGF) distribution to disrupt the normal pattern o f lens differentiation was evaluated by the production of transgenic m ice which express FGF-1 under the control of the lens-specific alpha A -crystallin promoter. Since FGF-1 lacks a classical signal peptide con sensus sequence, transgenic mice were also produced with a chimeric co nstruct containing the signal peptide sequence of the FGF-4 gene fused in frame to the coding sequences of the FGF-1 cDNA in order to obtain extracellular expression of the transgene. The presence of transgenic mRNA and protein was confirmed by in situ hybridization, Western anal ysis and immunohistochemistry. The ocular histology of newborn and you ng adult transgenic mice expressing FGF-1 without a signal peptide app eared normal. In contrast, mice expressing secreted FGF-I exhibited le ns abnormalities including the elongation of anterior epithelial cells . Epithelial cell elongation was accompanied by expression of the fibe r cell differentiation marker, beta-crystallin. These observations pro vide an in vivo demonstration that FGF-1 can induce anterior lens epit helial cells to express characteristics consistent with the onset of f iber cell differentiation. The transgenic induction of differentiation confirms that normal lens morphology reflects an asymmetric distribut ion of inductive factors within the eye.