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Cadherins are cell adhesion molecules with multiple morphogenic functions in brain development, for example, in neuroblast migration and aggregation, axon navigation, neural circuit formation, and synaptogenesis. More than 100 members of the cadherin superfamily are expressed in the developing and mature brain. Most of the cadherins investigated, in particular classic cadherins and δ-protocadherins, are expressed in the cerebellum. For several cadherin subtypes, expression begins at early embryonic stages and persists until mature stages of cerebellar development. At intermediate stages, distinct Purkinje cell clusters exhibit unique rostrocaudal and mediolateral expression profiles for each cadherin. In the chicken, mouse, and other species, the Purkinje cell clusters are separated by intervening raphes of migrating granule cells. This pattern of Purkinje cell clusters/raphes is, at least in part, continuous with the parasagittal striping pattern that is apparent in the mature cerebellar cortex, for example, for zebrin II/aldolase C. Moreover, subregions of the deep cerebellar nuclei, vestibular nuclei and the olivary complex also express cadherins differentially. Neuroanatomical evidence suggests that the nuclear subregions and cortical domains that express the same cadherin subtype are connected to each other, to form neural subcircuits of the cerebellar system. Cadherins thus provide a molecular code that specifies not only embryonic structures but also functional cerebellar compartmentalization. By following the implementation of this code, it can be revealed how mature functional architecture emerges from embryonic patterning during cerebellar development. Dysfunction of some cadherins is associated with psychiatric diseases and developmental impairments and may also affect cerebellar function.

The cerebellum shows remarkable variations in the relative size of its divisions among vertebrate species. In the present study, we compare the cerebella of two mammals (ferret and mouse) by mapping the expression of three cadherins (cadherin-8, protocadherin-7, and protocadherin-10) at similar postnatal stages. The three cadherins are expressed differentially in parasagittal stripes in the cerebellar cortex, in the portions of the deep cerebellar nuclei, in the divisions of the inferior olivary nucleus, and in the lateral vestibular nucleus. The expression profiles suggest that the cadherin-positive structures are interconnected. The expression patterns resemble each other in ferret and mouse, although some differences can be observed. The general resemblance indicates that cerebellar organization is based on a common set of embryonic divisions in the two species. Consequently, the large differences in cerebellar morphology between the two species are more likely caused by differential growth of these embryonic divisions than by differences in early embryonic patterning. Based on the cadherin expression patterns, a model of corticonuclear projection territories in ferret and mouse is proposed. In summary, our results indicate that the cerebellar systems of rodents and carnivores display a relatively large degree of similarity in their molecular and functional organization.

Fiber connections of the cerebellar cortex are organized into distinct parasagittal domains. Each domain expresses a unique subset of various genes. Brain structures that are directly connected to the cerebellar cortex, such as the deep cerebellar nuclei and the inferior olivary nucleus, show a similarly differential pattern of connectivity and gene expression. For example, several members of the cadherin family of adhesion molecules are expressed differentially in the subdivisions of the cerebellar system in chicken and mouse. Little is known, however, about how the molecular maps in the different parts of the cerebellum relate to each other in terms of connectivity. Here, we mapped the expression of three cadherins (cadherin-8, protocadherin-7, and protocadherin-10) in the cerebellar system of the chicken embryo. By simultaneously tracing axonal connections with biotinylated dextran amine, we demonstrate that cortical domains and deep nuclear portions as well as their fiber connections have a matching expression profile for protocadherin-10 in the posterior part of the cerebellum. Based on the tracing results for protocadherin-10 and the comparative expression mapping of all three cadherins, the cortical projection domains of the three deep cerebellar nuclei were determined in the posterior part of the cerebellum. Results were extrapolated to the rest of the cerebellar cortex. Our results provide direct experimental support for the notion that cadherins are markers for neural circuits in the brain. Moreover, we show that the expression pattern of all three cadherins confers unique identities to the Purkinje cell domains., (Copyright 2008 Wiley-Liss, Inc.)