A missed exit: Reelin sets in motion Dab1 polyubiquitination to put the break on neuronal migration: Figure 1.

Kerjan, Géraldine; Gleeson, Joseph G.

doi:10.1101/gad.1622907

Cited by 17 publications

(13 citation statements)

References 40 publications

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“…Regarding the mechanism of Dab1 downregulation during perinatal stages, it is well established that Reelin signaling through the adapter Dab1 leads to its tyrosine phosphorylation and subsequent ubiquitin-dependent degradation (Feng et al, 2007;Kerjan and Gleeson, 2007). Consistent with such Reelin-dependent Dab1 degradation, Dab1 protein levels are higher in reeler Reelin-deficient mice and lower in Reelin overexpressing mice than in wild-type mice (Feng et al, 2007;Kerjan and Gleeson, 2007;Pujadas et al, 2010).…”

Section: Discussionmentioning

confidence: 92%

Transient Downregulation of Dab1 Protein Levels during Development Leads to Behavioral and Structural Deficits: Relevance for Psychiatric Disorders

Teixeira¹,

Masachs²,

Muhaisen³

et al. 2013

Neuropsychopharmacol

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Psychiatric disorders have been hypothesized to originate during development, with genetic and environmental factors interacting in the etiology of disease. Therefore, developmentally regulated genes have received attention as risk modulators in psychiatric diseases. Reelin is an extracellular protein essential for neuronal migration and maturation during development, and its expression levels are reduced in psychiatric disorders. Interestingly, several perinatal insults that increase the risk of behavioral deficits alter Reelin signaling. However, it is not known whether a dysfunction in Reelin signaling during perinatal stages increases the risk of psychiatric disorders. Here we used a floxed dab1 allele to study whether a transient decrease in Dab1, a key component of the Reelin pathway, is sufficient to induce behavioral deficits related to psychiatric disorders. We found that transient Dab1 downregulation during perinatal stages leads to permanent abnormalities of structural layering in the neocortex and hippocampus. In contrast, conditional inactivation of the dab1 gene in the adult brain does not result in additional layering abnormalities. Furthermore, perinatal Dab1 downregulation causes behavior impairments in adult mice, such as deficits in memory, maternal care, pre-pulse inhibition, and response to cocaine. Some of these deficits were also found to be present in adolescence. We also show that D-cycloserine rescues the cognitive deficits observed in floxed dab1 mice with layering alterations in the hippocampus and neocortex. Our results indicate a causal relation between the downregulation of Dab1 protein levels during development and the structural and behavioral deficits associated with psychiatric diseases in the adult.

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Section: Discussionmentioning

confidence: 92%

Transient Downregulation of Dab1 Protein Levels during Development Leads to Behavioral and Structural Deficits: Relevance for Psychiatric Disorders

Teixeira¹,

Masachs²,

Muhaisen³

et al. 2013

Neuropsychopharmacol

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show abstract

“…Finally, recruitment of ubiquitin ligases to phosphorylated Dab1 results in ubiquitination of the protein, likely mediating the phosphorylation-dependent endocytosis of the entire Reelin signaling complex. With Reelin being targeted to the lysosome and Dab1 being degraded by the proteasome, the signal is terminated and the receptors recycle back to the membrane (Arnaud et al, 2003a;Bock et al, 2004;Suetsugu et al, 2004;Morimura et al, 2005;Kerjan and Gleeson, 2007).…”

Section: The Reelin Signaling Pathway In the Developing And Adult Brainmentioning

confidence: 99%

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

Knuesel

2010

Progress in Neurobiology

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“…Accumulation of Dab1 protein resulted in an excess of migrating neurons at the top of the cortical plate ("overmigration"). Reelin signaling, which induces Dab1 phosphorylation and ubiquitination, thus counteracts the promigratory role of Dab1 (Feng et al, 2007;Kerjan and Gleeson, 2007).…”

Section: Reelin Signaling Is Involved In Dynamic Changes Of the Actinmentioning

confidence: 99%

Reelin Stabilizes the Actin Cytoskeleton of Neuronal Processes by Inducing n-Cofilin Phosphorylation at Serine3

Chai¹,

Förster²,

Zhao³

et al. 2009

J. Neurosci.

192

190

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The extracellular matrix protein Reelin, secreted by Cajal-Retzius cells in the marginal zone of the cortex, controls the radial migration of cortical neurons. Reelin signaling involves the lipoprotein receptors apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR), the adapter protein Disabled1 (Dab1), and phosphatidylinositol-3-kinase (PI3K). Eventually, Reelin signaling acts on the cytoskeleton; however, these effects on cytoskeletal organization have remained elusive. In Reelin-deficient mutant mice, most cortical neurons are unable to migrate to their destinations, suggesting a role for Reelin signaling in the dynamic cytoskeletal reorganization that is required for neurons to migrate. Here, we show that Reelin signaling leads to serine3 phosphorylation of n-cofilin, an actin-depolymerizing protein that promotes the disassembly of F-actin. Phosphorylation at serine3 renders n-cofilin unable to depolymerize F-actin, thereby stabilizing the cytoskeleton. We provide evidence for ApoER2, Dab1, Src family kinases (SFKs), and PI3K to be involved in n-cofilin serine3 phosphorylation. Phosphorylation of n-cofilin takes place in the leading processes of migrating neurons as they approach the Reelin-containing marginal zone. Immunostaining for phospho-cofilin in dissociated reeler neurons is significantly increased after incubation in Reelin-containing medium compared with control medium. In a stripe choice assay, neuronal processes are stable on Reelin-coated stripes but grow on control stripes by forming lamellipodia. These novel findings suggest that Reelin-induced stabilization of neuronal processes anchors them to the marginal zone which appears to be required for the directional migration process.

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A missed exit: Reelin sets in motion Dab1 polyubiquitination to put the break on neuronal migration: Figure 1.

Cited by 17 publications

References 40 publications

Transient Downregulation of Dab1 Protein Levels during Development Leads to Behavioral and Structural Deficits: Relevance for Psychiatric Disorders

Transient Downregulation of Dab1 Protein Levels during Development Leads to Behavioral and Structural Deficits: Relevance for Psychiatric Disorders

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

Reelin Stabilizes the Actin Cytoskeleton of Neuronal Processes by Inducing n-Cofilin Phosphorylation at Serine3

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