The
cytoplasmic adaptor protein Disabled-1 (Dab1) is
necessary for the regulation of neuronal positioning in the developing brain by
the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein
E receptors ApoER2 and VLDL receptor induces tyrosine phosphorylation
of Dab1 and the subsequent activation or relocalization
of downstream targets like phosphatidylinositol-3 (PI3) kinase
and Nck. Disruption of Reelin
signalling leads to the accumulation of Dab1 protein
in the brains of genetically modified mice, suggesting that Reelin
limits its own action in responsive neurons by downregulating
the levels of Dab1 expression. Here, we use cultured primary embryonic neurons
as a model to demonstrate that Reelin treatment
targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3 kinase
activation is required for its proteasomal targeting.
Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dab1 degradation also depends on ApoER2 and
VLDL receptor in a gene-dose dependent manner. Moreover, pharmacological
blockade of the proteasome prevents the formation of
a proper cortical plate in an in vitro slice culture assay. Our results
demonstrate that signalling through neuronal ApoE receptors can activate the ubiquitin-proteasome
machinery, which might have implications for the role of Reelin
during neurodevelopment and in the regulation of synaptic transmission.
PMID: 15175346 [PubMed - as supplied by publisher]
Reelin
is a secreted glycoprotein that regulates neuronal positioning in cortical
brain structures through the VLDLR and ApoER2 receptors and the adaptor protein
Dab1. In addition to cellular disorganization, dendrite abnormalities are
present in the brain of reeler mice lacking Reelin. It is unclear whether these defects are due
primarily to cellular ectopia or the absence of Reelin. Here we examined dendrite development in the
hippocampus of normal and mutant mice and in dissociated cultures. We found
that dendrite complexity is severely reduced in homozygous mice deficient in Reelin signaling both in vivo and in vitro, and it is also
reduced in heterozygous mice in the absence of cellular ectopia.
Addition of Reelin interfering antibodies, receptor
antagonists, and Dab1 phosphorylation inhibitors
prevented dendrite outgrowth from normal neurons, whereas addition of
recombinant Reelin rescued the deficit in reeler cultures. Thus, the same signaling pathway controls
both neuronal migration and dendrite maturation.
PMID: 14715136 [PubMed - in process
Autism is a neurodevelopmental disorder characterized by stereotypic
and repetitive behavior and interests, together with social and communicative
deficiencies. The results of several genomic screens suggest the presence of an
autism susceptibility locus on chromosome 19p13.2-q13.4. The apolipoprotein E (APOE) gene on chromosome 19 encodes for a
protein, apoE, whose different isoforms
(E2, E3, E4) influence neuronal growth. APOE
participates in lipid transport and metabolism, repair, growth, and maintenance
of axons and myelin during neuronal development. The APOE protein competes with
the Reelin protein for VLDL/APOER2 receptor binding.
Several studies have reported evidence for an association between autism and
the Reelin gene. Based on these data we tested for
association between APOE and autism using family-based association methods in a
data set of 322 autism families. Three promoter, one intronic,
and one 3' UTR single nucleotide polymorphisms (SNPs)
in the APOE gene (-491a/t, -427c/t, -219g/t, 113c/g, and 5361c/t) as well as
the APOE functional polymorphism (E2, E3, E4) were examined and failed to
reveal significant evidence that autism is associated with APOE. Copyright 2003
Wiley-Liss, Inc.
