 |
||||
|
||||
|
||||
|
||||
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
This article has been cited by other articles:
B. A. Hatton, E. H. Villavicencio, K. D. Tsuchiya, J. I. Pritchard, S. Ditzler, B. Pullar, S. Hansen, S. E. Knoblaugh, D. Lee, C. G. Eberhart, et al.
The Smo/Smo Model: Hedgehog-Induced Medulloblastoma with 90% Incidence and Leptomeningeal Spread
Cancer Res., March 15, 2008; 68(6): 1768 - 1776.
[Abstract] [Full Text] [PDF]
D. Morales and M. E. Hatten
Molecular Markers of Neuronal Progenitors in the Embryonic Cerebellar Anlage.
J. Neurosci., November 22, 2006; 26(47): 12226 - 12236.
[Abstract] [Full Text] [PDF]
J. D. Corrales, S. Blaess, E. M. Mahoney, and A. L. Joyner
The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation
Development, May 1, 2006; 133(9): 1811 - 1821.
[Abstract] [Full Text] [PDF]
M. F. McManus and J. A. Golden
Topical Review: Neuronal Migration in Developmental Disorders
J Child Neurol, April 1, 2005; 20(4): 280 - 286.
[Abstract] [PDF]
K. Chen, P. G. Ochalski, T. S. Tran, N. Sahir, M. Schubert, A. Pramatarova, and B. W. Howell
Interaction between Dab1 and CrkII is promoted by Reelin signaling
J. Cell Sci., September 1, 2004; 117(19): 4527 - 4536.
[Abstract] [Full Text] [PDF]
M. F. McManus and J. A. Golden
Topical Review: Neuronal Migration in Developmental Disorders
J Child Neurol, March 1, 2004; 19(3): 280 - 286.
[Abstract] [PDF]
A. Pramatarova, P. G. Ochalski, K. Chen, A. Gropman, S. Myers, K.-T. Min, and B. W. Howell
Nck{beta} Interacts with Tyrosine-Phosphorylated Disabled 1 and Redistributes in Reelin-Stimulated Neurons
Mol. Cell. Biol., October 15, 2003; 23(20): 7210 - 7221.
[Abstract] [Full Text] [PDF]
E. Hartfuss, E. Forster, H. H. Bock, M. A. Hack, P. Leprince, J. M. Luque, J. Herz, M. Frotscher, and M. Gotz
Reelin signaling directly affects radial glia morphology and biochemical maturation
Development, October 1, 2003; 130(19): 4597 - 4609.
[Abstract] [Full Text] [PDF]
R. V. Sillitoe and R. Hawkes
Whole-mount Immunohistochemistry: A High-throughput Screen for Patterning Defects in the Mouse Cerebellum
J. Histochem. Cytochem., February 1, 2002; 50(2): 235 - 244.
[Abstract] [Full Text] [PDF]
H. Yang, P. Jensen, and D. Goldowitz
The Community Effect and Purkinje Cell Migration in the Cerebellar Cortex: Analysis of Scrambler Chimeric Mice
J. Neurosci., January 15, 2002; 22(2): 464 - 470.
[Abstract] [Full Text] [PDF]
V. Hammond, B. Howell, L. Godinho, and S.-S. Tan
disabled-1 Functions Cell Autonomously during Radial Migration and Cortical Layering of Pyramidal Neurons
J. Neurosci., November 15, 2001; 21(22): 8798 - 8808.
[Abstract] [Full Text] [PDF]
C. Costa, B. Harding, and A. J. Copp
Neuronal Migration Defects in the Dreher (Lmx1a) Mutant Mouse: Role of Disorders of the Glial Limiting Membrane
Cereb Cortex, June 1, 2001; 11(6): 498 - 505.
[Abstract] [Full Text] [PDF]
M. R. Roberts, K. Bittman, W.-W. Li, R. French, B. Mitchell, J. J. LoTurco, and S. R. D'Mello
The Flathead Mutation Causes CNS-Specific Developmental Abnormalities and Apoptosis
J. Neurosci., March 15, 2000; 20(6): 2295 - 2306.
[Abstract] [Full Text] [PDF]
D. S. Rice and T. Curran
Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS
Genes & Dev., November 1, 1999; 13(21): 2758 - 2773.
[Full Text]
T. Ohshima, E. C. Gilmore, G. Longenecker, D. M. Jacobowitz, R. O. Brady, K. Herrup, and A. B. Kulkarni
Migration Defects of cdk5-/- Neurons in the Developing Cerebellum is Cell Autonomous
J. Neurosci., July 15, 1999; 19(14): 6017 - 6026.
[Abstract] [Full Text] [PDF]
B. W. Howell, T. M. Herrick, and J. A. Cooper
Reelin-induced tryosine phosphorylation of Disabled 1 during neuronal positioning
Genes & Dev., March 15, 1999; 13(6): 643 - 648.
[Abstract] [Full Text]
V. Borrell, J. A. Del Rio, S. Alcantara, M. Derer, A. Martinez, G. D'Arcangelo, K. Nakajima, K. Mikoshiba, P. Derer, T. Curran, et al.
Reelin Regulates the Development and Synaptogenesis of the Layer-Specific Entorhino-Hippocampal Connections
J. Neurosci., February 15, 1999; 19(4): 1345 - 1358.
[Abstract] [Full Text] [PDF]
N Dahmane and A Ruiz-i-Altaba
Sonic hedgehog regulates the growth and patterning of the cerebellum
Development, January 6, 1999; 126(14): 3089 - 3100.
[Abstract] [PDF]
D. Rice, M Sheldon, G D'Arcangelo, K Nakajima, D Goldowitz, and T Curran
Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain
Development, January 9, 1998; 125(18): 3719 - 3729.
[Abstract] [PDF]
J. L. Gonzalez, C. J. Russo, D. Goldowitz, H. O. Sweet, M. T. Davisson, and C. A. Walsh
Birthdate and Cell Marker Analysis of Scrambler: A Novel Mutation Affecting Cortical Development with a Reeler-Like Phenotype
J. Neurosci., December 1, 1997; 17(23): 9204 - 9211.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|