Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype.
The reeler mutation in mice produces an especially well characterized disorder, with systematically abnormal migration of cerebral cortical neurons. The reeler gene encodes a large protein, termed Reelin, that in the cortex is synthesized and secreted exclusively in the Cajal-Retzius neurons of the cortical marginal zone (D'Arcangelo et al., 1995). In reeler mutant mice, loss of Reelin protein is associated with a systematic loss of the normal, "inside-out" sequence of neurogenesis in the cortex: neurons are formed in the normal sequence but become localized in the cortex in a somewhat inverted, although relatively disorganized "outside-in" pattern. Here we show that the scrambler mutant mouse exhibits a loss of lamination in the cortex and hippocampus that is indistinguishable from that seen in the reeler mouse. We use BrdU birthdating studies to show that scrambler cortex shows a somewhat inverted "outside-in" sequence of birthdates for cortical neurons that is similar to that previously described in reeler cortex. Finally, we perform staining with the CR-50 monoclonal antibody (Ogawa et al., 1995), which recognizes the Reelin protein (D'Arcangelo et al., 1997). We show that Reelin immunoreactivity is present in the scrambler cortex in a normal pattern, suggesting that Reelin is synthesized and released normally. Our data suggest that scrambler is a mutation in the same gene pathway as the reeler gene (Relnrl) and is most likely downstream of Relnrl.
González
J L
JL
Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Russo
C J
CJ
Goldowitz
D
D
Sweet
H O
HO
Davisson
M T
MT
Walsh
C A
CA
D000818:Animals; D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal / Q000032:analysis; D019070:Cell Lineage; D002465:Cell Movement; D002525:Cerebellar Cortex / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000032:analysis; D018507:Gene Expression Regulation, Developmental; D018740:Genetic Heterogeneity; D005865:Gestational Age; D006624:Hippocampus / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D009024:Morphogenesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000473:pathology*; D010641:Phenotype; D000091042:Reelin Protein; D012697:Serine Endopeptidases
D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases