Sonic hedgehog-mediated ventralization disrupts formation of the midbrain-hindbrain junction in the chick embryo

The secreted signaling molecule Sonic hedgehog (Shh) plays critical roles in pattern formation of the vertebrate central nervous system. During neurulation, Shh is produced by the ventral midline mesoderm as well as by the ventral neural tube, and its activity is required for the determination of ventral characteristics along the anterior-posterior neuraxis. The morphological boundary between midbrain and hindbrain, the isthmus, is an important tissue organizer that regulates the development of both the midbrain and the anterior hindbrain. In this study, we report that retrovirus-mediated misexpression of Shh in the early chick neural tube disrupts formation of the boundary between the midbrain and the hindbrain, and causes a fusion of the bilateral cerebellum primordia. Dorsally expressed Shh signals induce ectopic transcription of its receptor Ptc1 in the midbrain and the hindbrain. The expression of several genes (Noggin, Lmx1, BMP7) along the dorsal midline of the midbrain is abolished, and ventral or lateral markers (HNF3 beta, Ptc1, ELF1) are induced in the dorsal brain. Furthermore, the normally restricted expression of two genes (En1 and Pax2) in the mid/hindbrain junction region are expanded, reflecting the morphological defects. These results suggest that maintaining proper dorsal-ventral patterns of the neural tube is essential for normal development of the mid/hindbrain region.