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Previous Article | Next Article
Volume 17, Number 22, Issue of November 15, 1997 pp. 8767-8777
Cerebellar Disorganization Characteristic of Reeler in Scrambler Mutant Mice Despite Presence of Reelin
Received Aug. 4, 1997; accepted Aug. 7, 1997.
Dan Goldowitz1, Richard C. Cushing1, Eric Laywell1, Gabriella D'Arcangelo2, Michael Sheldon2, Hope O. Sweet3, Muriel Davisson3, Dennis Steindler1, and Tom Curran2 1 Department of Anatomy and Neurobiology, University of Tennessee College of Medicine, Memphis, Tennessee 38163, 2 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and 3 The Jackson Laboratory, Bar Harbor, Maine 04609
Analysis of the molecular basis of neuronal migration in the mammalian CNS relies critically on the discovery and identification of genetic mutations that affect this process. Here, we report the detailed cerebellar phenotype caused by a new autosomal recessive neurological mouse mutation, scrambler (gene symbol scm). The scrambler mutation results in ataxic mice that exhibit several neuroanatomic defects reminiscent of reeler. The most obvious of these lies in the cerebellum, which is small and lacks foliation. Granule cells, although normally placed in an internal granule cell layer, are greatly reduced in number (~20% of normal). Purkinje cells are also reduced in number, and the majority are located ectopically in deep cerebellar masses. There is a small population of Purkinje cells (~5% of the total) that occupy a Purkinje cell layer between the molecular and granule cell layers. Despite this apparent disorganization of Purkinje cells, zebrin-positive and zebrin-negative parasagittal zones can be delineated. The ectopic masses of Purkinje cells are bordered by the extracellular matrix protein tenascin and by processes containing glial fibrillary acidic protein. Antibodies specific for these proteins also identify a novel midline raphe structure in both scrambler and reeler cerebellum that is not present in wild-type mice. Thus, in many respects, the scrambler cerebellum is identical to that of reeler. However, the scrambler locus has been mapped to a site distinct from that of reelin (Reln), the gene responsible for the reeler defect. Here we find that there are normal levels of Reln mRNA in scrambler brain and that reelin protein is secreted normally by scrambler cerebellar cells. These findings imply that the scrambler gene product may function in a molecular pathway critical for neuronal migration that is tightly linked to, but downstream of, reelin.
Key words: scrambler; reeler; Purkinje cell; cerebellar granule cell; neuronal ectopia; neuronal migration; cerebellar mutants; reelin; disabled
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