The isthmic organizer and brain regionalization.

Distinct neural identities are acquired through progressive restriction of developmental potential under the influence of local environmental signals. Evidence for the localization of such morphogenetic signals at specific locations of the developing neural primordium has suggested the concept of "secondary organizer regions", which regulate the identity and regional polarity of neighboring neuroepithelial areas one step further. In recent years, the most studied secondary organizer has been the isthmic organizer, which is localized at the hind-midbrain transition and controls anterior hindbrain and midbrain regionalization. Otx2 and Gbx2 expression is fundamental for positioning the organizer and for the establishment of molecular interactions that induce Fgf8 expression and then, stabilize the autoregulative loop of En1, Wnt1 and Pax2 expression. Temporospatial patterns of such gene expressions are necessary for the correct development of the organizer which, by a planar mechanism of induction, controls the normal development of the rostral hindbrain from r2 to the midbrain-diencephalic boundary. Fgf8 appears as the active diffusible molecule for isthmic morphogenetic activity and has been suggested to be the morphogenetic effector in other inductive activities revealed in other neuroepithelial regions.