The concept of developmental compartments originated in studies of Drosophila embryogenesis. This review examines the hypothesis that the modular structure of the vertebrate cerebellum is strongly analogous to this earlier scheme. The pattern of cerebellar development, the adult circuitry, a variety of molecular markers expressed in specific subdivisions, and the phenotypes of several neurological mutations all provide abundant evidence that the vertebrate cerebellum is organized into modules. We present the case that, as a group, these markers reveal distinct boundaries that partition the cerebellum into true developmental compartments. Although this reductionist viewpoint advances our understanding of cerebellar organization, the relationship between these compartments and the functional behavior of the cerebellum remains a mystery.

Null alleles of the mouse Engrailed-2 gene, a molecular homolog of the fly gene engrailed, have demonstrable effects on the anteroposterior (A/P) patterning of cerebellum as reflected in the disruption of the normal process of foliation of the cerebellar cortex and the alteration of transgene expression boundaries in the adult. Engrailed-2 also affects the transient mediolateral (M/L) pattern of En-1 and Wnt-7b expression seen in late embryogenesis. We have examined three markers of cerebellar compartmentation in En-2 mutant mice: the Zebrin II and Ppath monoclonal antibodies and the transgene L7lacZ. In En-2 mutants, the normal temporal pattern of expression is preserved for all three markers, although the size and spatial location of various bands differ from those of the wild type. Unlike the foliation abnormalities, the M/L pattern disturbances we have found occur in nearly all cerebellar regions. Cell counts reveal that all major cell types of the olivocerebellar circuit are reduced by 30-40%. We propose that these results are best explained by a model in which the Engrailed-2 gene is involved in the early specification of the cerebellar field including the number of progenitors. Because each of these progenitors gives rise to a clone of defined size, Engrailed-2 helps specify adult cell number. We further postulate that the configuration of the seven Zebrin bands as well as the shapes and locations of the cerebellar lobules are set up by a second patterning event that occurs after neurogenesis is complete.

The complex behavioral symptoms and neuroanatomical abnormalities observed in autistic individuals strongly suggest a multi-factorial basis for this perplexing disease. Although not the perfect model, we believe the Engrailed genes provide an invaluable "window" into the elusive etiology of Autism Spectrum Disorder. The Engrailed-2 gene has been associated with autism in genetic linkage studies. The En2 knock-out mouse harbors cerebellar abnormalities that are similar to those found in autistic individuals and, as we report here, has a distinct anterior shift in the position of the amygdala in the cerebral cortex. Our initial analysis of background effects in the En1 mouse knock-out provides insight as to possible molecular mechanisms and gender differences associated with autism. These findings further the connection between Engrailed and autism and provide new avenues to explore in the ongoing study of the biological basis of this multifaceted disease.

No abstract

No abstract