Regulation and function of FGF8 in patterning of midbrain and anterior hindbrain

In this article, an adjunct to a platform presentation at the Winternationa l 2000 Symposium, we summarize the recent findings of this group concerning the regulation and functions of FGF8 expressed at the isthmus of the devel oping brain. We show that several different FGF8 isoforms, ectopically expr essed in midbrain or posterior forebrain, are able to mimic the proliferati ve and patterning functions previously attributed to the isthmus in tissue grafting studies. Moreover, we also show that FGF8 protein is sufficient to induce an ectopic isthmic organiser (Fgf-8+, Gbx2+) in anterior midbrain. We also provide evidence that isthmic FGF8 patterns anterior hindbrain, rep ressing Hox-a2 expression and setting aside a territory of the brain that i ncludes the cerebellar anlage. We show that these effects of FGF8 are likel y to be mediated via FGFR1 and be modulated by the putative FGF antagonist, Sprouty2, identified using a differential display screen. Finally, we prov ide evidence that the onset of Fgf8 expression is regulated by En1 and that its expression at the isthmus is subsequently maintained by a specific and direct interaction between rhombomere 1 and midbrain.