Fig. 9. FGF signaling is autoregulated at multiple levels and multiple FGF proteins regulate midbrain and cerebellum development. In the mouse, FGF8 expression in the isthmus at the four-somite stage represses the expression of Fgfr2 and Fgfr3 and activates the expression of Fgf18 at the five-somite stage. Fgf17 expression is initiated in a broader domain slightly later, and by E9 the three Fgfs are expressed in overlapping gradients radiating from the isthmus, whereas Fgfr2 and Fgfr3 are absent in this region. Spry1/2 genes are upregulated by FGFs. FGF8b is required to maintain a cascade of gene expression that includes absence of Otx2 in r1, allowing cerebellum development to occur. FGF17 and FGF18, and possibly FGF8a and a low level of FGF8b regulate growth and En expression in the midbrain.