Reelin and the Cerebellum

The cerebellum is a large, complex brain structure that mediates essential functions for movement, balance, cognition, and language (Ito, 2005). Development of the cerebellum critically depends on Reelin signaling. Complete deficiency of Reelin causes a severe cerebellar malformation, with extensive cellular disorganization and hypoplasia. Identical cerebellar defects are observed in mice lacking downstream components of the Reelin signaling pathway, including Reelin receptors VLDLR and ApoER2, adapter protein Dab1, or kinases Fyn and Src. The brain malformation results in ataxia and loss of balance, manifesting as a reeling gait in mice (hence the name Reelin) and multiple neurological problems in humans. More subtle abnormalities of Reelin signaling may underlie important neurobehavioral disorders in humans. In particular, some studies have linked RELN gene polymorphisms and reduced Reelin expression to autism. Since cerebellar defects are frequently observed in autistic brains, an attractive hypothesis is that Reelin signaling abnormalities may cause autism by perturbing cerebellar development or plasticity.

Despite growing biomedical significance, our understanding of how Reelin regulates cerebellar morphogenesis is far from complete. Reelin, its receptors, and downstream effectors are expressed by different cohorts of cells at different time points throughout cerebellar development. Most Reelin-producing cells are located near the surface of the developing cerebellar cortex, including cells of the rostral rhombic lip migratory stream (RLS), the nuclear transitory zone (NTZ), and the external granular layer (EGL). Other Reelin-producing cells are located deeper in the cerebellum, including some neurons of the deep cerebellar nuclei (DCN) and internal granular layer. Much evidence suggests that one important function of Reelin is to promote detachment of Purkinje cells from radial glia in the mantle zone of the embryonic cerebellar cortex, thus allowing multiple Purkinje cells to migrate along the same radial glia. The migrating Purkinje cells respond to Reelin signaling by activating a signaling cascade that includes Reelin receptors (VLDLR and ApoER2), adapter protein Dab1, and kinases Src and Fyn. Besides promoting Purkinje cell detachment from radial glia, Reelin may also regulate Purkinje cell spreading and monolayer formation, radial glia morphology, granule cell proliferation, unipolar brush cell migration, DCN cytoarchitecture, axon guidance, dendrite morphology, and synaptic plasticity. These mechanisms will require further basic research.