Signalling by FGF8 from the isthmus patterns anterior hindbrain and establishes the anterior limit of Hox gene expression

Current evidence suggests that the anterior segment of the vertebrate hindb rain, rhombomere 1, gives rise to the entire cerebellum. It is situated whe re two distinct developmental patterning mechanisms converge: graded signal ling from an organising centre (the isthmus) located at the midbrain/hindbr ain boundary confronts segmentation of the hindbrain. The unique developmen tal fate of rhombomere 1 is reflected by it being the only hindbrain segmen t in which no Hox genes are expressed, In this study we show that ectopic F GF8 protein, a candidate for the isthmic organising activity, is able to in duce and repress gene expression within the hindbrain in a manner appropria te to rhombomere 1. Using a heterotopic, heterospecific grafting strategy w e demonstrate that rhombomere 1 is able to express Hox genes but that both isthmic tissue and FGF8 inhibit their expression. Inhibition of FGF8 functi on in vivo shows that it is responsible for defining the anterior limit of Hox gene expression within the developing brain and thereby specifies the e xtent of the r1 territory. Previous studies have suggested that a retinoid morphogen gradient determines the axial limit of expression of individual H ox genes within the hindbrain. We propose a model whereby activation by ret inoids is antagonised by inhibition by FGF8 in the anterior hindbrain to se t aside the territory from which the cerebellum will develop.