Significance of F3/Contactin gene expression in cerebral cortex and nigrostriatal development.

F3/Contactin is a neuronal surface glycoprotein, which plays a general role in neural development and, in particular, in neuronal and oligodendrocyte differentiation. In a previous study using the F3/EGFP transgenic mice, which express an EGFP reporter under control of the regulatory region from the mouse F3/Contactin gene, the activation of the F3/Contactin promoter was found to correlate with granule and Purkinje neuron differentiation in developing cerebellar cortex. Here we report that in developing cerebral cortex and basal ganglia the F3/Contactin gene is mostly activated during early commitment of neuronal precursors, thus indicating a region-specific profile of its developmental activation. We also report that, in the same structures of F3/EGFP mice, a downregulation of the endogenous F3/Contactin gene occurs, which correlates with upregulation of the dopaminergic phenotype and with locomotor pattern abnormalities. Therefore, F3/EGFP transgenic mice exhibit morphological and functional phenotypes recapitulating those arising from imbalance of the striatal dopaminergic pathway. As for the underlying mechanisms, we postulate that in F3/EGFP mice F3/Contactin downregulation results from the ability of transgene promoter sequences to interfere with the activation of the endogenous gene, thus realizing an F3/Contactin knockdown model, while dopaminergic upregulation is consistent with a general F3/Contactin inhibitory effect on the neuronal phenotype.