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1.
Sci Adv ; 10(13): eadn9998, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38536915

ABSTRACT

Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor cells and their lineages. We identified multiple RGC classes that initiate parallel lineages, converging onto a common class of newborn neuron. Parallel RGC classes and transcriptomic trajectories were repeated across germinal zones and conserved in ferret and human, but not in mouse. Neurons followed parallel differentiation trajectories in the gyrus and sulcus, with different expressions of human cortical malformation genes. Progenitor cell lineage multiplicity is conserved in the folded mammalian cerebral cortex.


Subject(s)
Cerebral Cortex , Ferrets , Animals , Mice , Humans , Cell Lineage/physiology , Neurons/physiology , Cell Differentiation , Neurogenesis
2.
Sci Adv ; 9(48): eadi3728, 2023 12.
Article in English | MEDLINE | ID: mdl-38019920

ABSTRACT

Barrel cortex integrates contra- and ipsilateral whiskers' inputs. While contralateral inputs depend on the thalamocortical innervation, ipsilateral ones are thought to rely on callosal axons. These are more abundant in the barrel cortex region bordering with S2 and containing the row A-whiskers representation, the row lying nearest to the facial midline. Here, we ask what role this callosal axonal arrangement plays in ipsilateral tactile signaling. We found that novel object exploration with ipsilateral whiskers confines c-Fos expression within the highly callosal subregion. Targeting this area with in vivo patch-clamp recordings revealed neurons with uniquely strong ipsilateral responses dependent on the corpus callosum, as assessed by tetrodotoxin silencing and by optogenetic activation of the contralateral hemisphere. Still, in this area, stimulation of contra- or ipsilateral row A-whiskers evoked an indistinguishable response in some neurons, mostly located in layers 5/6, indicating their involvement in the midline representation of the whiskers' sensory space.


Subject(s)
Cerebral Cortex , Corpus Callosum , Corpus Callosum/physiology , Neurons/physiology , Axons , Touch/physiology
3.
Cell Rep ; 18(5): 1157-1170, 2017 01 31.
Article in English | MEDLINE | ID: mdl-28147272

ABSTRACT

Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3) as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.


Subject(s)
GABAergic Neurons/metabolism , Interneurons/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Animals , Cell Movement/physiology , Cerebral Cortex/metabolism , Mice , Mice, Inbred C57BL , Neuregulins , Pyramidal Cells/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, ErbB-4/metabolism , Signal Transduction/physiology
4.
Neuron ; 79(6): 1152-68, 2013 Sep 18.
Article in English | MEDLINE | ID: mdl-24050403

ABSTRACT

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.


Subject(s)
Action Potentials/genetics , Brain/pathology , ErbB Receptors/deficiency , Interneurons/physiology , Phenotype , Schizophrenia , Action Potentials/physiology , Animals , Animals, Newborn , Brain/physiopathology , Cognition Disorders/etiology , Cognition Disorders/genetics , Disease Models, Animal , Electroporation , ErbB Receptors/genetics , Glutamate Decarboxylase/metabolism , Green Fluorescent Proteins/genetics , In Vitro Techniques , LIM-Homeodomain Proteins/genetics , Male , Maze Learning/physiology , Mice , Mice, Transgenic , Motor Activity/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Parvalbumins/metabolism , Patch-Clamp Techniques , Proteins/genetics , Proteins/metabolism , RNA, Untranslated , Receptor, ErbB-4 , Receptors, GABA-A/metabolism , Schizophrenia/complications , Schizophrenia/genetics , Schizophrenia/pathology , Social Behavior , Statistics as Topic , Synaptic Transmission/genetics , Transcription Factors/genetics
5.
Neuron ; 76(2): 338-52, 2012 Oct 18.
Article in English | MEDLINE | ID: mdl-23083737

ABSTRACT

Neurogenesis relies on a delicate balance between progenitor maintenance and neuronal production. Progenitors divide symmetrically to increase the pool of dividing cells. Subsequently, they divide asymmetrically to self-renew and produce new neurons or, in some brain regions, intermediate progenitor cells (IPCs). Here we report that central nervous system progenitors express Robo1 and Robo2, receptors for Slit proteins that regulate axon guidance, and that absence of these receptors or their ligands leads to loss of ventricular mitoses. Conversely, production of IPCs is enhanced in Robo1/2 and Slit1/2 mutants, suggesting that Slit/Robo signaling modulates the transition between primary and intermediate progenitors. Unexpectedly, these defects do not lead to transient overproduction of neurons, probably because supernumerary IPCs fail to detach from the ventricular lining and cycle very slowly. At the molecular level, the role of Slit/Robo in progenitor cells involves transcriptional activation of the Notch effector Hes1. These findings demonstrate that Robo signaling modulates progenitor cell dynamics in the developing brain.


Subject(s)
Cell Proliferation , Central Nervous System/cytology , Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Receptors, Immunologic/metabolism , Signal Transduction/physiology , Stem Cells/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cadherins/metabolism , Cell Count , Cell Cycle/genetics , Cells, Cultured , Central Nervous System/embryology , Chi-Square Distribution , Embryo, Mammalian , Gene Expression Regulation, Developmental/genetics , Green Fluorescent Proteins/genetics , Homeodomain Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Neocortex/cytology , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neurogenesis , Neurons/physiology , Receptors, Immunologic/deficiency , Signal Transduction/genetics , Transcription Factor HES-1 , Transfection , Roundabout Proteins
6.
Nat Neurosci ; 14(3): 305-13, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21297631

ABSTRACT

Cell migration is the consequence of the sum of positive and negative regulatory mechanisms. Although appropriate migration of neurons is a principal feature of brain development, the negative regulatory mechanisms remain obscure. We found that JNK1 was highly active in developing cortex and that selective inhibition of JNK in the cytoplasm markedly increased both the frequency of exit from the multipolar stage and radial migration rate and ultimately led to an ill-defined cellular organization. Moreover, regulation of multipolar-stage exit and radial migration in Jnk1(-/-) (also known as Mapk8) mice, resulted from consequential changes in phosphorylation of the microtubule regulator SCG10 (also called stathmin-2). Expression of an SCG10 mutant that mimics the JNK1-phosphorylated form restored normal migration in the brains of Jnk1(-/-) mouse embryos. These findings indicate that the phosphorylation of SCG10 by JNK1 is a fundamental mechanism that governs the transition from the multipolar stage and the rate of neuronal cell movement during cortical development.


Subject(s)
Cell Movement/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Neurons/physiology , Animals , Calcium-Binding Proteins , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Cerebral Cortex/growth & development , Cerebral Cortex/metabolism , Gene Expression Regulation , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Mitogen-Activated Protein Kinase 8/genetics , Mitogen-Activated Protein Kinase 8/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Stathmin , Tubulin/metabolism
7.
EMBO J ; 29(18): 3170-83, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20676059

ABSTRACT

The development of the nervous system is a time-ordered and multi-stepped process that requires neural specification, axonal navigation and arbor refinement at the target tissues. Previous studies have demonstrated that the transcription factor Zic2 is necessary and sufficient for the specification of retinal ganglion cells (RGCs) that project ipsilaterally at the optic chiasm midline. Here, we report that, in addition, Zic2 controls the refinement of eye-specific inputs in the visual targets by regulating directly the expression of the serotonin transporter (Sert), which is involved in the modulation of activity-dependent mechanisms during the wiring of sensory circuits. In agreement with these findings, RGCs that express Zic2 ectopically show defects in axonal refinement at the visual targets and respond to pharmacological blockage of Sert, whereas Zic2-negative contralateral RGCs do not. These results link, at the molecular level, early events in neural differentiation with late activity-dependent processes and propose a mechanism for the establishment of eye-specific domains at the visual targets.


Subject(s)
Axons/physiology , Gene Expression Regulation, Developmental , Retinal Ganglion Cells/physiology , Serotonin Plasma Membrane Transport Proteins/genetics , Transcription Factors/physiology , Animals , Biomarkers/metabolism , Blotting, Western , Chromatin Immunoprecipitation , Female , Gene Expression Profiling , Immunoenzyme Techniques , Mice , Mice, Knockout , Oligonucleotide Array Sequence Analysis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Serotonin Plasma Membrane Transport Proteins/metabolism
8.
Development ; 135(10): 1833-41, 2008 May.
Article in English | MEDLINE | ID: mdl-18417618

ABSTRACT

Axons of retinal ganglion cells (RGCs) make a divergent choice at the optic chiasm to cross or avoid the midline in order to project to ipsilateral and contralateral targets, thereby establishing the binocular visual pathway. The zinc-finger transcription factor Zic2 and a member of the Eph family of receptor tyrosine kinases, EphB1, are both essential for proper development of the ipsilateral projection at the mammalian optic chiasm midline. Here, we demonstrate in mouse by functional experiments in vivo that Zic2 is not only required but is also sufficient to change the trajectory of RGC axons from crossed to uncrossed. In addition, our results reveal that this transcription factor regulates the expression of EphB1 in RGCs and also suggest the existence of an additional EphB1-independent pathway controlled by Zic2 that contributes to retinal axon divergence at the midline.


Subject(s)
Axons/physiology , Nuclear Proteins/physiology , Optic Chiasm/cytology , Receptor, EphB1/physiology , Transcription Factors/physiology , Animals , Female , Green Fluorescent Proteins/metabolism , Humans , Mice , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Optic Chiasm/embryology , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/metabolism , Transcription Factors/biosynthesis , Transcription Factors/genetics
9.
Front Biosci ; 13: 1646-53, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-17981656

ABSTRACT

In animals with binocular vision, retinal fibers either project across the midline or they remain on the same side of the ventral diencephalon, forming an X-shaped commissure known as the optic chiasm. The correct formation of the optic chiasm during development is essential to establish a fully functional visual system. Visual dysfunction associated with axonal misrouting at the optic chiasm has been described in albino individuals and in patients with non-decussating retinal-fugal fiber syndrome. Although little is known about the causes of retinal misrouting in these conditions, the molecular mechanisms responsible for the formation of the optic chiasm are beginning to be elucidated in vertebrates. This review focuses on our current knowledge of how the optic chiasm forms, which will hopefully help us to better understand these congenital anomalies.


Subject(s)
Optic Chiasm/embryology , Optic Chiasm/physiology , Animals , Axons/metabolism , Body Patterning , Diencephalon/metabolism , Drosophila , Gene Expression Regulation, Developmental , Hedgehog Proteins/metabolism , Homeodomain Proteins/metabolism , Humans , Mice , Models, Biological , Retina/embryology , Retina/metabolism , Signal Transduction
10.
BMC Dev Biol ; 7: 103, 2007 Sep 17.
Article in English | MEDLINE | ID: mdl-17875204

ABSTRACT

BACKGROUND: The neural retina is a highly structured tissue of the central nervous system that is formed by seven different cell types that are arranged in layers. Despite much effort, the genetic mechanisms that underlie retinal development are still poorly understood. In recent years, large-scale genomic analyses have identified candidate genes that may play a role in retinal neurogenesis, axon guidance and other key processes during the development of the visual system. Thus, new and rapid techniques are now required to carry out high-throughput analyses of all these candidate genes in mammals. Gene delivery techniques have been described to express exogenous proteins in the retina of newborn mice but these approaches do not efficiently introduce genes into the only retinal cell type that transmits visual information to the brain, the retinal ganglion cells (RGCs). RESULTS: Here we show that RGCs can be targeted for gene expression by in utero electroporation of the eye of mouse embryos. Accordingly, using this technique we have monitored the morphology of electroporated RGCs expressing reporter genes at different developmental stages, as well as their projection to higher visual targets. CONCLUSION: Our method to deliver ectopic genes into mouse embryonic retinas enables us to follow the course of the entire retinofugal pathway by visualizing RGC bodies and axons. Thus, this technique will permit to perform functional studies in vivo focusing on neurogenesis, axon guidance, axon projection patterning or neural connectivity in mammals.


Subject(s)
Gene Expression Regulation, Developmental , Gene Transfer Techniques , Retinal Ganglion Cells , Animals , Electroporation , Embryo, Mammalian , Female , Genes, Reporter , Mice , Mice, Inbred C57BL , Morphogenesis , Pregnancy
11.
Brain Res Mol Brain Res ; 122(2): 133-50, 2004 Mar 30.
Article in English | MEDLINE | ID: mdl-15010206

ABSTRACT

In an attempt to elucidate the molecular basis of neuronal migration and corticogenesis, we performed subtractive hybridization of mRNAs from the upper cortical layers (layer I and upper cortical plate) against mRNAs from the remaining cerebral cortex at E15-E16. We obtained a collection of subtracted cDNA clones and analyzed their 3' UTR sequences, 47% of which correspond to EST sequences, and may represent novel products. Among the cloned sequences, we identified gene products that have not been reported in brain or in the cerebral cortex before. We examined the expression pattern of 39 subtracted clones, which was enriched in the upper layers of the cerebral cortex at embryonic stages. The expression of most clones is developmentally regulated, and especially high in embryonic and early postnatal stages. Four of the unknown clones were studied in more detail and identified as a new member of the tetraspanin superfamily, a putative RNA binding protein, a specific product of the adult dentate gyrus and a protein containing a beta-catenin repeat. We thus cloned a collection of subtracted cDNAs coding for protein products that may be involved in the development of the cerebral cortex.


Subject(s)
Cell Differentiation/genetics , Cell Movement/genetics , Cerebral Cortex/embryology , DNA, Complementary/genetics , Nerve Tissue Proteins/genetics , Neurons/metabolism , Amino Acid Sequence , Animals , Animals, Newborn , Base Sequence , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , DNA, Complementary/isolation & purification , Dentate Gyrus/cytology , Dentate Gyrus/embryology , Dentate Gyrus/metabolism , Female , Fetus , Genomic Library , Growth Substances/genetics , Growth Substances/isolation & purification , Membrane Proteins/genetics , Membrane Proteins/isolation & purification , Mice , Molecular Sequence Data , Nerve Tissue Proteins/isolation & purification , Neurons/cytology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/isolation & purification , Sequence Homology, Amino Acid , Sequence Homology, Nucleic Acid
12.
Gene Expr Patterns ; 3(6): 777-83, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14643687

ABSTRACT

HCN4 is a hyperpolarization-activated nucleotide-gated cation channel involved in the generation of the I(f) current that drives cardiac pacemaker activity. Previous studies have demonstrated that HCN4 is highly expressed in a restricted manner in adult sinoatrial (SA) node [Eur. J. Biochem. 268 (2001) 1646]. However, its developmental expression pattern is unknown. We have examined expression of HCN4 mRNA during mouse heart development. HCN4 mRNA was first detected in the cardiac crescent at embryonic day (ED) 7.5. At ED 8 it was symmetrically located in the most caudal portion of the heart tube, the sinus venosus where pacemaker activity has previously been reported [Am. J. Physiol. 212 (1967) 407]. With further development, HCN4 expression became asymmetrically distributed, occupying the dorsal wall of the right atria, and was progressively restricted to the junction of the right atrial appendage and the superior vena cava. The site of HCN4 expression in late embryonic heart coincided with the location of the SA node in postnatal and adult heart [Cardiovasc. Res. 52 (2001) 51]. Our results suggest that HCN4 may be a unique marker of the developing SA node.


Subject(s)
Heart/embryology , Ion Channels/metabolism , Mice/embryology , Animals , Cyclic Nucleotide-Gated Cation Channels , Gene Expression , Heart/anatomy & histology , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , In Situ Hybridization , Ion Channels/genetics , Mice/genetics , Mice/metabolism , Myocardium/metabolism , RNA, Messenger/analysis , RNA, Messenger/metabolism
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