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Cited by 378Neurogenesis and neuroplasticity mechanismsAxon Guidance and Neuronal SignalingDevelopmental Biology and Gene Regulation

Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain

Rice, Dennis S., Sheldon, Michael, D’Arcangelo, Gabriella, Nakajima, Kazunori, Goldowitz, Dan, Curran, Tom·1998·Development
DOI 10.1242/dev.125.18.3719
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Abstract

Mutation of either reelin (Reln) or disabled-1 (Dab1) results in widespread abnormalities in laminar structures throughout the brain and ataxia in reeler and scrambler mice. Both exhibit the same neuroanatomical defects, including cerebellar hypoplasia with Purkinje cell ectopia and disruption of neuronal layers in the cerebral cortex and hippocampus. Despite these phenotypic similarities, Reln and Dab1 have distinct molecular properties. Reln is a large extracellular protein secreted by Cajal-Retzius cells in the forebrain and by granule neurons in the cerebellum. In contrast, Dab1 is a cytoplasmic protein which has properties of an adapter protein that functions in phosphorylation-dependent intracellular signal transduction. Here, we show that Dab1 participates in the same developmental process as Reln. In scrambler mice, neuronal precursors are unable to invade the preplate of the cerebral cortex and consequently, they do not align within the cortical plate. During development, cells expressing Dab1 are located next to those secreting Reln at critical stages of formation of the cerebral cortex, cerebellum and hippocampus, before the first abnormalities in cell position become apparent in either reeler or scrambler. In reeler, the major populations of displaced neurons contain elevated levels of Dab1 protein, although they express normal levels of Dab1 mRNA. This suggests that Dab1 accumulates in the absence of a Reln-evoked signal. Taken together, these results indicate that Dab1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain.

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  • In wild-type neurons, NOVA2 represses both exon 7b and 7c of the Dab1 transcript, and the resulting DAB1 protein isoform DAB1Δ7bc is subject to ubiquitylation upon Reelin activation.

    “In wild-type neurons, NOVA2 represses both exon 7b and 7c of the Dab1 transcript, and the resulting DAB1 protein isoform DAB1Δ7bc is subject to ubiquitylation upon Reelin activation43–45.”

    From The neurogenetics of alternative splicing (2016) · cites this paper as [43]

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Authors
Rice, D. S., Sheldon, M., D’Arcangelo, G., Nakajima, K., Goldowitz, D., & Curran, T.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • RIKEN (JP)
Corresponding author
Curran, Tom
ORCID
Venue
Development
Publisher
The Company of Biologists
Published
1998-09-15
Volume
125
Issue
18
Pages
3719-3729
ISSN
  • 0950-1991 (ISSN-L)
  • 1477-9129
DOI
10.1242/dev.125.18.3719
OpenAlex
W2119766505
Cited by
378
References
57
Citations by year
2026: 2 · 2025: 8 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 8 · 2019: 4 · 2018: 4 · 2017: 12 · 2016: 15 · 2015: 15 · 2014: 13 · 2013: 11 · 2012: 20
FWCI
6.60
Type
journal article
Language
en
Open access
closed
Licence
www.biologists.com/user-licence-1-1/ (vor)
Locations
  • Development (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (T32CA09346, T32CA009346, P 30CA 21765, P30CA021765)
  • National Institute of Neurological Disorders and Stroke (R01 NS36558, R01NS036558)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Disabled-1, reelin, cortical lamination, reeler mice, cerebellar hypoplasia, cortical development, hippocampus development, neuronal precursors, adaptor proteins, ataxia, Cajal-Retzius cells
MeSH terms
Reelin Protein, Animals, Brain, Cerebellum, Cerebral Cortex, Hippocampus, Mice, Inbred C3H, Mice, Neurologic Mutants, Nerve Tissue Proteins, Phosphoproteins, Serine Endopeptidases, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, In Situ Hybridization, Mice

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