EARLY MESENCEPHALON METENCEPHALON PATTERNING AND DEVELOPMENT OF THE CEREBELLUM/

Experimental studies in chick and analysis of mouse mutants have provi ded a framework for studying the early developmental processes involve d in specifying the cerebellar anlage. Fate mapping studies in chick h ave shown that at early stages the cerebellum derives from cells in th e mesencephalon and metencephalon (mes-met). Transplantation studies i n chick have implicated the mes-met junction (isthmus) as a source of secreted factors that organize development of the entire mes-met, perh aps by stimulating proliferation and specifying positional values acro ss the region. Fgf-8 has been implicated as a major factor involved in the isthmus organizing activity. Gene expression studies indicate tha t the anterior and posterior expression domains of the homeobox genes Otx-2 and Gbx-2, respectively, are the earliest indication of a divisi on of the brain. Furthermore, the Otx-2/Gbx-2 expression border later resides at the mes-met junction. Genetic studies in mouse have shown t hat Otx-2 and Gbx-2 are required for normal development of cells on bo th sides of the border. In addition, mutations affecting the secreted factor Wnt-1, which is expressed anterior to the Otn-2/Gbx-2 expressio n border and the homeodomain transcription factors, Engrailed-1,2 and Pax-2,5 that have broad overlapping expression domains in the mes-met, result in deletions of mes-met structures. Taken together, these stud ies suggest that specification of the cerebellar territory requires a hierarchy of complex cellular and genetic interactions that gradually subdivide the brain into smaller regions.