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1.
Nat Commun ; 10(1): 4249, 2019 09 18.
Article in English | MEDLINE | ID: mdl-31534164

ABSTRACT

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density.


Subject(s)
Apoptosis/physiology , Interneurons/metabolism , Neurogenesis/physiology , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Animals , Central Nervous System/cytology , Central Nervous System/embryology , Female , GABAergic Neurons/cytology , Homeodomain Proteins/metabolism , Interneurons/cytology , Male , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Oligodendroglia/cytology
2.
Dev Biol ; 432(1): 24-33, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28625870

ABSTRACT

Transcription factors are key orchestrators of the emergence of neuronal diversity within the developing spinal cord. As such, the two paralogous proteins Pax3 and Pax7 regulate the specification of progenitor cells within the intermediate neural tube, by defining a neat segregation between those fated to form motor circuits and those involved in the integration of sensory inputs. To attain insights into the molecular means by which they control this process, we have performed detailed phenotypic analyses of the intermediate spinal interneurons (IN), namely the dI6, V0D, V0VCG and V1 populations in compound null mutants for Pax3 and Pax7. This has revealed that the levels of Pax3/7 proteins determine both the dorso-ventral extent and the number of cells produced in each subpopulation; with increasing levels leading to the dorsalisation of their fate. Furthermore, thanks to the examination of mutants in which Pax3 transcriptional activity is skewed either towards repression or activation, we demonstrate that this cell diversification process is mainly dictated by Pax3/7 ability to repress gene expression. Consistently, we show that Pax3 and Pax7 inhibit the expression of Dbx1 and of its repressor Prdm12, fate determinants of the V0 and V1 interneurons, respectively. Notably, we provide evidence for the activity of several cis-regulatory modules of Dbx1 to be sensitive to Pax3 and Pax7 transcriptional activity levels. Altogether, our study provides insights into how the redundancy within a TF family, together with discrete dynamics of expression profiles of each member, are exploited to generate cellular diversity. Furthermore, our data supports the model whereby cell fate choices in the neural tube do not rely on binary decisions but rather on inhibition of multiple alternative fates.


Subject(s)
Homeodomain Proteins/physiology , Interneurons/physiology , Nerve Tissue Proteins/physiology , PAX3 Transcription Factor/physiology , PAX7 Transcription Factor/physiology , Spinal Cord/cytology , Animals , Cell Differentiation/physiology , Chick Embryo , Gene Expression Regulation, Developmental , Interneurons/cytology , Mice , Neural Tube/physiology , Spinal Cord/embryology , Stem Cells/cytology , Stem Cells/physiology
3.
Cereb Cortex ; 27(10): 4701-4718, 2017 10 01.
Article in English | MEDLINE | ID: mdl-27620979

ABSTRACT

Loss of neurons in the neocortex is generally thought to result in a final reduction of cerebral volume. Yet, little is known on how the developing cerebral cortex copes with death of early-born neurons. Here, we tackled this issue by taking advantage of a transgenic mouse model in which, from early embryonic stages to mid-corticogenesis, abundant apoptosis is induced in the postmitotic compartment. Unexpectedly, the thickness of the mutant cortical plate at E18.5 was normal, due to an overproduction of upper layer neurons at E14.5. We developed and simulated a mathematical model to investigate theoretically the recovering capacity of the system and found that a minor increase in the probability of proliferative divisions of intermediate progenitors (IPs) is a powerful compensation lever. We confirmed experimentally that mutant mice showed an enhanced number of abventricular progenitors including basal radial glia-like cells and IPs. The latter displayed increased proliferation rate, sustained Pax6 expression and shorter cell cycle duration. Altogether, these results demonstrate the remarkable plasticity of neocortical progenitors to adapt to major embryonic insults via the modulation of abventricular divisions thereby ensuring the production of an appropriate number of neurons.


Subject(s)
Cell Proliferation/physiology , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Neurons/cytology , Animals , Cell Death , Gene Expression Regulation, Developmental/physiology , Mice, Transgenic , Neural Stem Cells/cytology , Neurogenesis/physiology
4.
Cell Rep ; 17(12): 3133-3141, 2016 12 20.
Article in English | MEDLINE | ID: mdl-28009284

ABSTRACT

Cajal-Retzius cells (CRs), the first-born neurons in the developing cerebral cortex, coordinate crucial steps in the construction of functional circuits. CRs are thought to be transient, as they disappear during early postnatal life in both mice and humans, where their abnormal persistence is associated with pathological conditions. Embryonic CRs comprise at least three molecularly and functionally distinct subtypes: septum, ventral pallium/pallial-subpallial boundary (PSB), and hem. However, whether subtype-specific features exist postnatally and through which mechanisms they disappear remain unknown. We report that CR subtypes display unique distributions and dynamics of death in the postnatal mouse cortex. Surprisingly, although all CR subtypes undergo cell death, septum, but not hem, CRs die in a Bax-dependent manner. Bax-inactivated rescued septum-CRs maintain immature electrophysiological properties. These results underlie the existence of an exquisitely refined control of developmental cell death and provide a model to test the effect of maintaining immature circuits in the adult neocortex.


Subject(s)
Cell Death/genetics , Cerebral Cortex/metabolism , Neurons/metabolism , bcl-2-Associated X Protein/metabolism , Animals , Animals, Newborn , Cell Differentiation/genetics , Cell Lineage/genetics , Cerebral Cortex/embryology , Cerebral Cortex/growth & development , Embryo, Mammalian , Humans , Mice
5.
Curr Biol ; 25(19): 2466-78, 2015 Oct 05.
Article in English | MEDLINE | ID: mdl-26387718

ABSTRACT

In the neocortex, higher-order areas are essential to integrate sensory-motor information and have expanded in size during evolution. How higher-order areas are specified, however, remains largely unknown. Here, we show that the migration and distribution of early-born neurons, the Cajal-Retzius cells (CRs), controls the size of higher-order areas in the mouse somatosensory, auditory, and visual cortex. Using live imaging, genetics, and in silico modeling, we show that subtype-specific differences in the onset, speed, and directionality of CR migration determine their differential invasion of the developing cortical surface. CR migration speed is cell autonomously modulated by vesicle-associated membrane protein 3 (VAMP3), a classically non-neuronal mediator of endosomal recycling. Increasing CR migration speed alters their distribution in the developing cerebral cortex and leads to an expansion of postnatal higher-order areas and congruent rewiring of thalamo-cortical input. Our findings thus identify novel roles for neuronal migration and VAMP3-dependent vesicular trafficking in cortical wiring.


Subject(s)
Cell Movement/physiology , Cerebral Cortex/physiology , Interstitial Cells of Cajal/physiology , Neocortex/physiology , Neurons/metabolism , Animals , Cerebral Cortex/cytology , Interstitial Cells of Cajal/cytology , Mice , Mice, Transgenic , Models, Biological , Neocortex/cytology , Neocortex/metabolism , Vesicle-Associated Membrane Protein 3/metabolism
6.
PLoS One ; 6(12): e28497, 2011.
Article in English | MEDLINE | ID: mdl-22174821

ABSTRACT

Short interspersed repetitive elements (SINEs) are highly repeated sequences that account for a significant proportion of many eukaryotic genomes and are usually considered "junk DNA". However, we previously discovered that many AmnSINE1 loci are evolutionarily conserved across mammalian genomes, suggesting that they may have acquired significant functions involved in controlling mammalian-specific traits. Notably, we identified the AS021 SINE locus, located 390 kbp upstream of Satb2. Using transgenic mice, we showed that this SINE displays specific enhancer activity in the developing cerebral cortex. The transcription factor Satb2 is expressed by cortical neurons extending axons through the corpus callosum and is a determinant of callosal versus subcortical projection. Mouse mutants reveal a crucial function for Sabt2 in corpus callosum formation. In this study, we compared the enhancer activity of the AS021 locus with Satb2 expression during telencephalic development in the mouse. First, we showed that the AS021 enhancer is specifically activated in early-born Satb2(+) neurons. Second, we demonstrated that the activity of the AS021 enhancer recapitulates the expression of Satb2 at later embryonic and postnatal stages in deep-layer but not superficial-layer neurons, suggesting the possibility that the expression of Satb2 in these two subpopulations of cortical neurons is under genetically distinct transcriptional control. Third, we showed that the AS021 enhancer is activated in neurons projecting through the corpus callosum, as described for Satb2(+) neurons. Notably, AS021 drives specific expression in axons crossing through the ventral (TAG1(-)/NPY(+)) portion of the corpus callosum, confirming that it is active in a subpopulation of callosal neurons. These data suggest that exaptation of the AS021 SINE locus might be involved in enhancement of Satb2 expression, leading to the establishment of interhemispheric communication via the corpus callosum, a eutherian-specific brain structure.


Subject(s)
Conserved Sequence/genetics , Corpus Callosum/cytology , Enhancer Elements, Genetic/genetics , Mammals/genetics , Matrix Attachment Region Binding Proteins/genetics , Neurons/metabolism , Short Interspersed Nucleotide Elements/genetics , Transcription Factors/genetics , Animals , Animals, Newborn , Base Sequence , Binding Sites , Embryonic Development/genetics , Gene Expression Regulation, Developmental , Genetic Loci/genetics , Matrix Attachment Region Binding Proteins/metabolism , Mice , Mice, Transgenic , Molecular Sequence Data , Neurons/cytology , Organ Specificity/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Synteny/genetics , Transcription Factors/metabolism , beta-Galactosidase/metabolism
7.
J Neurosci ; 30(31): 10563-74, 2010 Aug 04.
Article in English | MEDLINE | ID: mdl-20685999

ABSTRACT

The generation of a precise number of neural cells and the determination of their laminar fate are tightly controlled processes during development of the cerebral cortex. Using genetic tracing in mice, we have identified a population of glutamatergic neurons generated by Dbx1-expressing progenitors at the pallial-subpallial boundary predominantly at embryonic day 12.5 (E12.5) and subsequent to Cajal-Retzius cells. We show that these neurons migrate tangentially to populate the cortical plate (CP) at all rostrocaudal and mediolateral levels by E14.5. At birth, they homogeneously populate cortical areas and represent <5% of cortical cells. However, they are distributed into neocortical layers according to their birthdates and express the corresponding markers of glutamatergic differentiation (Tbr1, ER81, Cux2, Ctip2). Notably, this population dies massively by apoptosis at the completion of corticogenesis and represents 50% of dying neurons in the postnatal day 0 cortex. Specific genetic ablation of these transient Dbx1-derived CP neurons leads to a 20% decrease in neocortical cell numbers in perinatal animals. Our results show that a previously unidentified transient population of glutamatergic neurons migrates from extraneocortical regions over long distance from their generation site and participates in neocortical radial growth in a non-cell-autonomous manner.


Subject(s)
Cell Movement/physiology , Glutamic Acid/metabolism , Neocortex/metabolism , Neurons/metabolism , Animals , Apoptosis/physiology , Cell Count , Immunohistochemistry , Mice , Neocortex/embryology , Neurogenesis/physiology , Reverse Transcriptase Polymerase Chain Reaction , Vesicular Glutamate Transport Protein 2/metabolism , gamma-Aminobutyric Acid/metabolism
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