Obstructed migration of Purkinje cells in the developing cerebellum of the reeler mutant mouse

Abstract

It has been considered that cortical malformation in the brain of the reeler mutant mouse is due to a defect in the process of neuroblast migration during development. We examined the process of Purkinje cell migration in the cerebellar primordium of the reeler mutant immunohistochemically and electron-microscopically, employing a specific marker for Purkinje cells and markers for radial glia. To facilitate the recognition of the homozygote of the reeler mutation (r1) at the embryonic stage, we introduced the chromosome carrying the autosomal semi-dominant mutation, hammer-toe (Hm), by crossbreeding and backcross into the heterozygote of the reeler mutation, which is an autosomal recessive and located on the homologous chromosome. Using this double heterozygous strain (+/rl-Hm/+), the homozygote of rl can be selected from littermates by the normal appearance of the feet. Both the heterozygous rl embryos and non-carriers harbor the Hm locus and show the Hm phenotype as a deformity of the feet that can be recognized from the 15th day of gestation. In the cerebellar primordium of control mice, Purkinje cells migrated radially from the ventricular zone towards the cortex. In contrast, most of the migratory Purkinje cells remained in the intermediate zone, and their migration towards the cortex was obstructed in the cerebellum of the reeler mutant. A disorganized arrangement of both the processes and cell bodies of the radial glia was demonstrated in the cerebellar primordium of the reeler by labeling them with the antibody against tenascin, a neuron-glial adhesion molecule, and the monoclonal antibody 1D11, a marker for immature astroglia. Electron-microscopic observations revealed apposition of the migratory cells to the radially oriented glial processes in the intermediate zone of the control cerebellum. In contrast, the apposition of leading processes of the migratory neuroblasts to disorganized processes of the radial glia was observed in the intermediate zone of the reeler cerebellum. These findings suggest that the obstructed migration and disordered cortical alignment of Purkinje cells in the reeler cerebellum is due to dysgenesis and abnormal development of radial glia, resulting in disturbance of contact guidance in the process of Purkinje cell migration.

Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells

“…For instance, in Reeler mice, there is a reduced proliferation of external granular cells that causes a defect in PC migration (28). Another example is the lurcher mouse, which has a gain of function of glutamate receptor ionotropic delta 2, resulting in death of PCs that lead to a secondary loss of CGNs (29).…”

Regulation of Purkinje Cell Alignment by Reelin as Revealed with CR-50 Antibody

“…1 D), when the first sign of Purkinje cell derangement is noted in reeler mice (Goffinet, 1983). Because the difference in the arrangement pattern of Purkinje cells between the two phenotypes is recognized clearly by late embryonic days (Yuasa et al, 1993) (Fig. 1A), and the following cerebellar development seems to amplify this difference, the initial relationships of Purkinje cells with Reelin itself or Reelin-related signals may be critical for their positioning.…”

“…Consequently, a zone in which they should normally form their layer would be occupied by other cells, such as astroglial cells having migrated outwardly or descending granule cells. The reeler Purkinje cells would be deep in subcortical areas, away from the expanding cerebellar surface, with a clustered pattern probably attributable to their own homophilic adhesive properties and /or "obstruction" mechanisms (Pinto-Lord et al, 1982;Yuasa et al, 1993).…”

“…It is unclear how these Purkinje cells form their layer (Rakic, 1990;Hatten and Heintz, 1995). The reeler mouse mutant (Falconer, 1951; for review, see Caviness and Rakic, 1978;Goffinet, 1984Goffinet, , 1995Rakic and Caviness, 1995) is useful for studying this unknown cytoarchitectural mechanism, because most Purkinje cells in the cerebellum of reeler mice are not arranged in the monolayer as observed in the cerebellar cortex of normal mice but are instead clustered in subcortical areas (Mariani et al, 1977;Mikoshiba et al, 1980;Goffinet, 1983;Yuasa et al, 1993) (Fig. 1 A-C).…”

Misplacement of Purkinje Cells during Postnatal Development in Bax Knock-Out Mice: A Novel Role for Programmed Cell Death in the Nervous System?

“…Therefore, the accurate migration and survival of a subset of PCs is essential for normal cerebellar development, including the generation of sufficient numbers of granule cells. The importance of PCs in these events is clearly demonstrated in Reelin null mice that exhibit reduced proliferation of EGCs in the face of aberrant PC migration (Yuasa et al, 1993;Miyata et al, 1997).…”