I want my neurons to migrate to the correct location. How is your doctor directing that migration?
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0081711
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Conor O'Leary
equal contributor,
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Stacey J. Cole
equal contributor,
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Michael Langford,
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Jayani Hewage,
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Amanda White,
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Helen M. Cooper
mail
- Published: Nov 27, 2013
- DOI: 10.1371/journal.pone.0081711
Abstract
The
etiology of neuropsychiatric disorders, including schizophrenia and
autism, has been linked to a failure to establish the intricate neural
network comprising excitatory pyramidal and inhibitory interneurons
during neocortex development. A large proportion of cortical inhibitory
interneurons originate in the medial ganglionic eminence (MGE) of the
ventral telencephalon and then migrate through the ventral
subventricular zone, across the corticostriatal junction, into the
embryonic cortex. Successful navigation of newborn interneurons through
the complex environment of the ventral telencephalon is governed by
spatiotemporally restricted deployment of both chemorepulsive and
chemoattractive guidance cues which work in concert to create a
migratory corridor. Despite the expanding list of interneuron guidance
cues, cues responsible for preventing interneurons from re-entering the
ventricular zone of the ganglionic eminences have not been well
characterized. Here we provide evidence that the chemorepulsive axon
guidance cue, RGMa (Repulsive Guidance Molecule a), may fulfill this
function. The ventricular zone restricted expression of
RGMa in
the ganglionic eminences and the presence of its receptor, Neogenin, in
the ventricular zone and on newborn and maturing MGE-derived
interneurons implicates RGMa-Neogenin interactions in interneuron
differentiation and migration. Using an
in vitro approach, we show that RGMa promotes interneuron differentiation by potentiating neurite outgrowth. In addition, using
in vitro
explant and migration assays, we provide evidence that RGMa is a
repulsive guidance cue for newborn interneurons migrating out of the
ganglionic eminence ventricular zone. Intriguingly, the alternative
Neogenin ligand, Netrin-1, had no effect on migration. However, we
observed complete abrogation of RGMa-induced chemorepulsion when newborn
interneurons were simultaneously exposed to RGMa and Netrin-1
gradients, suggesting a novel mechanism for the tight regulation of
RGMa-guided interneuron migration. We propose that during peak
neurogenesis, repulsive RGMa-Neogenin interactions drive interneurons
into the migratory corridor and prevent re-entry into the ventricular
zone of the ganglionic eminences.
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