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Section MOLECULAR NEUROSCIENCE
The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), whose asymmetric division give birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers endoplasmic reticulum stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a hitherto unrecognized contribution of UPR to cell fate acquisition during mammalian brain development.
Reference
1. Developmental Cell (2015) Laguesse et al.
Establishing Neuronal Identity in the Cerebral Cortex
C. Hanashima*
Riken center for developmental biology, kobe, Japan. * Presenting e-mail: hanashima@cdb.riken.jp
The functional integrity of the brain system relies on the precisely coordinated production of diverse neurons and their placement along the three-dimensional axis. Specifically in the cerebral cortex, progenitor cells produce distinct neuronal subtypes in a stereotypical order and establish a six-layer structure, which are further modified into functional areas. A prevailing view concerning the neurogenesis of the neocortex is that, neural stem cells undergo successive rounds of asymmetric cell divisions to produce the principal layer subtypes: preplate, deep-layer, and upper-layer neurons, through a progressive restriction in cell competence. Consistent with this view, we previously showed that foxg1, a forkhead transcription factor expressed in the telencephalon, plays a central role in establishing early gene network and switching neurogenesis from preplate cells to deep-layer neurons. However, our recent studies have also indicated that the specification and integration of neocortical neurons may rely on communication between distinct cell types, in addition to intrinsic transcriptional regulation. Here, i would like to present our findings on the mechanisms by which ne-ocortical subtype identities establish in the neocortex, by manipulating gene expression and number of neurogenesis in the developing mouse cortex. Our results indicate that neocortical progenitors integrate both intrinsic and extrinsic cues to generate distinct layer neurons, a system which ultimately balances the production of neocortical subtypes during development and possibly evolution.
References
1. T. Kumamoto, et al. Cell rep., 2013, 3(3), 931-945.
2. K. Toma, et al. J. Neurosci., 2014, 34(39):13259-76.
3. K. Toma, et al. Front. Neurosci., 2015, 9:274.
Laminar Cell Fate in the Neocortex: Can We Change it?
Victor Tarabykin*
Lobachevsky University, Nizhny Novgorod, Russia. * Presenting e-mail: victor.tarabykin@charite.de
Neocortical projection neurons are generated by two types of progenitors. While early progenitors give rise to deep layer neurons, late progenitors are restricted to produce upper layer neurons. Molecular mechanism that controls different potential of early versus late progenitors is not known. Here, we report that the high expression level of TrkC-T1; a non-catalytic splice variant of the neurotrophin receptor-TrkC, distinguishes early from late neocortical progenitors that express low TrkC-T1 level. We also provide direct evidence that the high level of TrkC-T1 promotes deep layers
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OM&P
OM&P
Section MOLECULAR NEUROSCIENCE
neurogenesis, while low level allows upper layers generation. We further show that TrkC-T1 controls neocortical cell fate by preventing activation of adapter molecule ShcA, which in turn leads to inhibition of MAP kinase pathway. Manipulating the levels of activity of TrkC-T1, ShcA or Erk has a direct effect on fate determination of cortical progenitors. We further demonstrate that down-regulation of TrkC-T1 levels in late progenitors allows activation of ShcA with consecutive activation of Erk (MAP kinase) and instructs late progenitors to generate upper layer neurons.
Molecular Mechanisms Underlying Area-Specific Circuit Formation in the Mouse Neocortex
Michele Studer*
Institute of Biology Valrose, France. * Presenting e-mail: michele.studer@unice.fr
Despite an apparently similar laminar and cell-type organization, neocortical areas have distinct features in terms of molecular identity, morphology and long-range connectivity of residing projection neurons, leading ultimately to area-specific circuits. Despite its well-defined anatomical character and functional significance, the molecular mechanisms by which neuronal subtypes are specified within cortical layers and across domains as well as their precise assembly into distinct functional neocortical areas, remains largely unknown. Since neocortical areas are first pre-patterned by a set of transcription factors expressed in gradients during development and then acquire a distinct function postnatally (sensory-input versus motor-output), a complex interplay between intrinsic and extrinsic activity-dependent mechanisms might exist during formation of area-specific circuits. This talk will focus on how factors expressed in distinct prospective areas and layers control the ratio and distribution of projection neuron subtypes (intracortical versus subcortical) and how these factors modulate activity-dependent mechanisms in the motor and somatosensory postnatal cortex. Together with epigenetic modifications, we propose that the great variety of projection neurons in the mammalian cerebral cortex is not only due to the existence of genetic programs directing the development of each single neuronal subtype, but also to mechanisms that modify and refine after birth the processes specifying major projection neuron classes. Overall, our data contribute in unraveling some of the developmental mechanisms of how diverse populations of cortical projection neurons are coordinated into high-functional territories and how they interact during assembly of cortical circuits into distinct functional areas.
References
1. Harb K., Magrinelli E., Nicolas C.S, Lukianets N., Frangeul L., Pietri M., Sun T., Sandoz G., Grammont F., Jabaudon D., Studer M.* and Alfano C.* Area-specific development of distinct neocortical neuron subclasses is regulated by postnatal epigenetic modifications. eLife, 2016, Jan 27;5.
2. Alfano C., Magrinelli E., Harb K., Hevner R. F. and Studer M. Postmitotic control of sensory area specification during neocortical development. Nature Communications, 2014 Dec 5;5:5632.
3. Tomassy Srubek G., De Leonibus E., Jabaudon D., Lodato S., Alfano C., Mele A., Macklis J.D. and Studer M. Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI. PNAS, 2010, 107(8): 3576-81.
Behavioral Characterization of SATB 1 (+/-) Heterozygous Mice
I.I. Belousova*, E.A. Epifanova, A.A. Babaev, I.V. Mukhina, V.S. Tarabykin
Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia. * Presenting e-mail: ira.belousova@gmail.com
Satb1 (special AT-rich sequence binding protein 1) gene encodes a matrix protein that regulates chromatin structure and gene expression. In the present study, Satb1 heterozygous (+/-) mice were investigated to unravel the functional role of Satb1 in the brain.
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