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1.
Med Sci (Paris) ; 36 Hors série n° 2: 13-16, 2020 Dec.
Article in French | MEDLINE | ID: mdl-33427630

ABSTRACT

Diseases of the locomotor system are at the origin of disabilities with severe social and economic consequences. The study of the neuromuscular system development and maintenance has become a key challenge for the scientific community in order to design efficient therapies. My thesis project aims to elucidate the mechanisms at the origin of the communication between motoneuron axons and their muscle targets in order to understand how specific innervations are generated during development and maintained during adulthood. The first part of the project will address the understanding of the mechanisms controlling the specific muscle-axon recognition during development. I will perform live imaging and fixed tissues experiments to visualize and understand the development of myoblasts and motoneurons at the same time. Then, I will perform transcriptomic experiments to discover molecules playing a role in the specific axon-muscle recognition. The second part of the project is meant to elucidate the mechanism controlling the system maintenance in the adult. To answer this question I will study the function of morphological transcription factors in adulthood, which are known as transcription factors controlling the morphology of motoneurons during development. To conclude, this project will lead to novel biological concepts that will increase our fundamental knowledge on developmental biology. Understanding the mechanisms that specify the muscle innervation will allow to find efficient ways to tackle neuromuscular diseases.


Subject(s)
Muscle, Skeletal/growth & development , Muscle, Skeletal/physiology , Regeneration/physiology , Adult , Animals , Axons/physiology , CRISPR-Cas Systems , Gene Expression Regulation, Developmental , Genomics/methods , Humans , Motor Neurons/physiology , Muscle, Skeletal/innervation , RNA-Seq , Regeneration/genetics
2.
Cell Rep ; 17(6): 1473-1481, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27806288

ABSTRACT

During spinal cord development, astrocyte precursors arise from neuroepithelial progenitors, delaminate from the ventricular zone, and migrate toward their final locations where they differentiate. Although the mechanisms underlying their early specification and late differentiation are being deciphered, less is known about the temporal control of their migration. Here, we show that the epithelial-mesenchymal transition regulator Zeb1 is expressed in glial precursors and report that loss of Zeb1 function specifically delays the onset of astrocyte precursor delamination from the ventricular zone, correlating with transient deregulation of the adhesion protein Cadherin-1. Consequently, astrocyte precursor invasion into the Zeb1-/- mutant white matter is delayed, and induction of their differentiation is postponed. These findings illustrate how fine regulation of adhesive properties influences the onset of neural precursor migration and further support the notion that duration of exposure of migrating astrocyte precursors to environmental cues and/or their correct positioning influence the timing of their differentiation.


Subject(s)
Astrocytes/cytology , Astrocytes/metabolism , Cell Movement , Spinal Cord/cytology , Stem Cells/cytology , Stem Cells/metabolism , Zinc Finger E-box-Binding Homeobox 1/metabolism , Aging/genetics , Animals , Body Patterning , Cell Differentiation , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Gene Expression Regulation, Developmental , Mice , Mutation/genetics
3.
Dev Cell ; 33(3): 343-50, 2015 May 04.
Article in English | MEDLINE | ID: mdl-25942625

ABSTRACT

Dorsal root ganglia (DRG) sensory neurons arise from heterogeneous precursors that differentiate in two neurogenic waves, respectively controlled by Neurog2 and Neurog1. We show here that transgenic mice expressing a Zeb1/2 dominant-negative form (DBZEB) exhibit reduced numbers of nociceptors and altered pain sensitivity. This reflects an early impairment of Neurog1-dependent neurogenesis due to the depletion of specific sensory precursor pools, which is slightly later partially compensated by the contribution of boundary cap cells (BCCs). Indeed, combined DBZEB expression and genetic BCCs ablation entirely deplete second wave precursors and, in turn, nociceptors, thus recapitulating the Neurog1(-/-) neuronal phenotype. Altogether, our results uncover roles for Zeb family members in the developing DRGs; they show that the Neurog1-dependent sensory neurogenesis can be functionally partitioned in two successive phases; and finally, they illustrate plasticity in the developing peripheral somatosensory system supported by the BCCs, thereby providing a rationale for sensory precursor diversity.


Subject(s)
Homeodomain Proteins/metabolism , Kruppel-Like Transcription Factors/metabolism , Neuronal Plasticity/physiology , Nociceptors/metabolism , Repressor Proteins/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/deficiency , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation/physiology , Ganglia, Spinal/embryology , Ganglia, Spinal/metabolism , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Kruppel-Like Transcription Factors/genetics , Mice, Transgenic , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/metabolism , Neurogenesis/genetics , Neurogenesis/physiology , Neuronal Plasticity/genetics , Repressor Proteins/genetics , Zinc Finger E-box Binding Homeobox 2 , Zinc Finger E-box-Binding Homeobox 1
4.
Dev Biol ; 383(2): 264-74, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24056079

ABSTRACT

Axon fasciculation is one of the processes controlling topographic innervation during embryonic development. While axon guidance steers extending axons in the accurate direction, axon fasciculation allows sets of co-extending axons to grow in tight bundles. The Eph:ephrin family has been involved both in axon guidance and fasciculation, yet it remains unclear how these two distinct types of responses are elicited. Herein we have characterized the role of ephrin-B1, a member of the ephrinB family in sensory and motor innervation of the limb. We show that ephrin-B1 is expressed in sensory axons and in the limb bud mesenchyme while EphB2 is expressed in motor and sensory axons. Loss of ephrin-B1 had no impact on the accurate dorso-ventral innervation of the limb by motor axons, yet EfnB1 mutants exhibited decreased fasciculation of peripheral motor and sensory nerves. Using tissue-specific excision of EfnB1 and in vitro experiments, we demonstrate that ephrin-B1 controls fasciculation of axons via a surround repulsion mechanism involving growth cone collapse of EphB2-expressing axons. Altogether, our results highlight the complex role of Eph:ephrin signaling in the development of the sensory-motor circuit innervating the limb.


Subject(s)
Axons/physiology , Ephrin-B1/metabolism , Motor Neurons/physiology , Receptors, Eph Family/metabolism , Sensory Receptor Cells/physiology , Signal Transduction , Animals , Cells, Cultured , Embryo, Mammalian/metabolism , Ephrin-B2/metabolism , Extremities/embryology , Extremities/innervation , Ganglia, Spinal/metabolism , Growth Cones/metabolism , Mesoderm/metabolism , Mice , Mice, Inbred C57BL , Motor Neurons/metabolism , Mutation/genetics , Sensory Receptor Cells/metabolism
5.
PLoS One ; 6(6): e21213, 2011.
Article in English | MEDLINE | ID: mdl-21695052

ABSTRACT

Genes of the coe (collier/olfactory/early B-cell factor) family encode Helix-Loop-Helix transcription factors that are widely conserved in metazoans and involved in many developmental processes, neurogenesis in particular. Whereas their functions during vertebrate neural tube formation have been well documented, very little is known about their expression and role during central nervous system (CNS) development in protostomes. Here we characterized the CNS expression of coe genes in the insect Drosophila melanogaster and the polychaete annelid Platynereis dumerilii, which belong to different subgroups of protostomes and show strikingly different modes of development. In the Drosophila ventral nerve cord, we found that the Collier-expressing cells form a subpopulation of interneurons with diverse molecular identities and neurotransmitter phenotypes. We also demonstrate that collier is required for the proper differentiation of some interneurons belonging to the Eve-Lateral cluster. In Platynereis dumerilii, we cloned a single coe gene, Pdu-coe, and found that it is exclusively expressed in post mitotic neural cells. Using an original technique of in silico 3D registration, we show that Pdu-coe is co-expressed with many different neuronal markers and therefore that, like in Drosophila, its expression defines a heterogeneous population of neurons with diverse molecular identities. Our detailed characterization and comparison of coe gene expression in the CNS of two distantly-related protostomes suggest conserved roles of coe genes in neuronal differentiation in this clade. As similar roles have also been observed in vertebrates, this function was probably already established in the last common ancestor of all bilaterians.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Differentiation , Central Nervous System/cytology , Drosophila melanogaster/genetics , Gene Expression Regulation , Neurons/cytology , Polychaeta/genetics , Animals , Central Nervous System/growth & development , Central Nervous System/metabolism , Central Nervous System/physiology , Drosophila melanogaster/cytology , Drosophila melanogaster/growth & development , Drosophila melanogaster/physiology , Interneurons/cytology , Interneurons/metabolism , Multigene Family/genetics , Neuronal Plasticity/genetics , Neurons/metabolism , Polychaeta/cytology , Polychaeta/growth & development , Polychaeta/physiology , Time Factors
6.
Stem Cells ; 27(11): 2722-33, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19785035

ABSTRACT

In humans and rodents the adult spinal cord harbors neural stem cells located around the central canal. Their identity, precise location, and specific signaling are still ill-defined and controversial. We report here on a detailed analysis of this niche. Using microdissection and glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP) transgenic mice, we demonstrate that neural stem cells are mostly dorsally located GFAP(+) cells lying ependymally and subependymally that extend radial processes toward the pial surface. The niche also harbors doublecortin protein (Dcx)(+) Nkx6.1(+) neurons sending processes into the lumen. Cervical and lumbar spinal cord neural stem cells maintain expression of specific rostro-caudal Hox gene combinations and the niche shows high levels of signaling proteins (CD15, Jagged1, Hes1, differential screening-selected gene aberrative in neuroblastoma [DAN]). More surprisingly, the niche displays mesenchymal traits such as expression of epithelial-mesenchymal-transition zinc finger E-box-binding protein 1 (ZEB1) transcription factor and smooth muscle actin. We found ZEB1 to be essential for neural stem cell survival in vitro. Proliferation within the niche progressively ceases around 13 weeks when the spinal cord reaches its final size, suggesting an active role in postnatal development. In addition to hippocampus and subventricular zone niches, adult spinal cord constitutes a third central nervous system stem cell niche with specific signaling, cellular, and structural characteristics that could possibly be manipulated to alleviate spinal cord traumatic and degenerative diseases.


Subject(s)
Glial Fibrillary Acidic Protein/metabolism , Homeodomain Proteins/metabolism , Kruppel-Like Transcription Factors/metabolism , Spinal Cord/cytology , Spinal Cord/metabolism , Stem Cell Niche/cytology , Stem Cell Niche/metabolism , Stem Cells/cytology , Actins/metabolism , Animals , Cell Proliferation , Doublecortin Protein , Gene Expression Regulation, Developmental , Glial Fibrillary Acidic Protein/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Mice , Mice, Transgenic , Neurons/cytology , Neurons/metabolism , Stem Cells/metabolism , Zinc Finger E-box-Binding Homeobox 1
7.
EMBO J ; 28(20): 3228-43, 2009 Oct 21.
Article in English | MEDLINE | ID: mdl-19745814

ABSTRACT

In Drosophila subperineurial glia (SPG) ensheath and insulate the nerve. SPG is under strict cell cycle and survival control because cell division or death of such a cell type would compromise the integrity of the blood-nerve barrier. The mechanisms underlying the survival of SPG remain unknown. Here, we show that the embryonic peripheral glia expresses the Zfh1 transcription factor, and in zfh1 mutants a particular SPG subtype, ePG10, undergoes apoptosis. Our findings show that in ePG10, Zfh1 represses the pro-apoptotic RHG-motif gene reaper in a cell-autonomous manner. Zfh1 also blocks the activation of the Jun N-terminal kinase (JNK) pathway, and reducing or enhancing JNK signalling in zfh1 mutants prevents or promotes ePG10 apoptosis. Our study shows a novel function for Zfh1 as an anti-apoptotic molecule and uncovers a cryptic JNK-dependent apoptotic programme in ePG10, which is normally blocked by Zfh1. We propose that, in cells such as SPG that do not undergo self-renewal and survive long periods, transcriptional control of RHG-motif gene expression together with fine tuning of JNK signalling is crucial for cell survival.


Subject(s)
Apoptosis/physiology , Drosophila Proteins/physiology , Drosophila melanogaster/physiology , JNK Mitogen-Activated Protein Kinases/physiology , Neuroglia/cytology , Neuroglia/metabolism , Repressor Proteins/physiology , Animals , Apoptosis/genetics , Blotting, Western , Cell Differentiation/genetics , Cell Differentiation/physiology , Drosophila Proteins/genetics , Drosophila melanogaster/enzymology , Drosophila melanogaster/metabolism , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/physiology , JNK Mitogen-Activated Protein Kinases/genetics , Peripheral Nervous System/metabolism , Repressor Proteins/genetics , Signal Transduction/genetics , Signal Transduction/physiology
8.
Neuron ; 64(6): 857-70, 2009 Dec 24.
Article in English | MEDLINE | ID: mdl-20064392

ABSTRACT

Low-threshold mechanoreceptor neurons (LTMs) of the dorsal root ganglia (DRG) are essential for touch sensation. They form highly specialized terminations in the skin and display stereotyped projections in the spinal cord. Functionally defined LTMs depend on neurotrophin signaling for their postnatal survival and functioning, but how these neurons arise during development is unknown. Here, we show that specific types of LTMs can be identified shortly after DRG genesis by unique expression of the MafA transcription factor, the Ret receptor and coreceptor GFRalpha2, and find that their specification is Ngn2 dependent. In mice lacking Ret, these LTMs display early differentiation defects, as revealed by reduced MafA expression, and at later stages their central and peripheral projections are compromised. Moreover, in MafA mutants, a discrete subset of LTMs display altered expression of neurotrophic factor receptors. Our results provide evidence that genetic interactions involving Ret and MafA progressively promote the differentiation and diversification of LTMs.


Subject(s)
Ganglia, Spinal/metabolism , Maf Transcription Factors, Large/metabolism , Mechanoreceptors/metabolism , Proto-Oncogene Proteins c-ret/metabolism , Sensory Receptor Cells/metabolism , Touch/physiology , Afferent Pathways/cytology , Afferent Pathways/embryology , Afferent Pathways/metabolism , Animals , Cell Differentiation/genetics , Ganglia, Spinal/cytology , Ganglia, Spinal/embryology , Gene Expression Regulation, Developmental/genetics , Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Maf Transcription Factors, Large/genetics , Mechanoreceptors/cytology , Mice , Mice, Knockout , Mice, Transgenic , Mutation/genetics , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Neurogenesis/genetics , Proto-Oncogene Proteins c-ret/genetics , Sensory Receptor Cells/cytology , Sensory Thresholds/physiology , Signal Transduction/genetics
9.
BMC Neurosci ; 8: 97, 2007 Nov 19.
Article in English | MEDLINE | ID: mdl-18021428

ABSTRACT

BACKGROUND: The different sensory modalities temperature, pain, touch and muscle proprioception are carried by somatosensory neurons of the dorsal root ganglia. Study of this system is hampered by the lack of molecular markers for many of these neuronal sub-types. In order to detect genes expressed in sub-populations of somatosensory neurons, gene profiling was carried out on wild-type and TrkA mutant neonatal dorsal root ganglia (DRG) using SAGE (serial analysis of gene expression) methodology. Thermo-nociceptors constitute up to 80 % of the neurons in the DRG. In TrkA mutant DRGs, the nociceptor sub-class of sensory neurons is lost due to absence of nerve growth factor survival signaling through its receptor TrkA. Thus, comparison of wild-type and TrkA mutants allows the identification of transcripts preferentially expressed in the nociceptor or mechano-proprioceptor subclasses, respectively. RESULTS: Our comparison revealed 240 genes differentially expressed between the two tissues (P < 0.01). Some of these genes, CGRP, Scn10a are known markers of sensory neuron sub-types. Several potential markers of sub-populations, Dok4, Crip2 and Grik1/GluR5 were further analyzed by quantitative RT-PCR and double labeling with TrkA,-B,-C, c-ret, parvalbumin and isolectin B4, known markers of DRG neuron sub-types. Expression of Grik1/GluR5 was restricted to the isolectin B4+ nociceptive population, while Dok4 and Crip2 had broader expression profiles. Crip2 expression was however excluded from the proprioceptor sub-population. CONCLUSION: We have identified and characterized the detailed expression patterns of three genes in the developing DRG, placing them in the context of the known major neuronal sub-types defined by molecular markers. Further analysis of differentially expressed genes in this tissue promises to extend our knowledge of the molecular diversity of different cell types and forms the basis for understanding their particular functional specificities.


Subject(s)
Ganglia, Spinal/physiology , Gene Expression Regulation/physiology , Genetic Testing/methods , Neurons/physiology , Animals , Animals, Newborn , Mice , Mice, Mutant Strains
10.
Eur J Neurosci ; 24(1): 37-44, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16882006

ABSTRACT

Barh1/h2 genes encode two related homeobox transcription factors (B-H1 and B-H2) previously shown to play essential roles in the formation and specification of the distal leg segments and in retinal neurogenesis. Here we describe the restricted expression pattern of the B-H1/-H2 homeoprotein within the embryonic ventral nerve cord of Drosophila. We show that B-H1/-H2 are specifically expressed in a subset of dopaminergic neurons, namely the unpaired ventral midline dopaminergic neuron, and in a subpopulation of laterally projecting motoneurons, i.e. the five motoneurons forming the segmental nerve a (SNa) branch. Using the GAL4-UAS system we show that B-H1/-H2(Gal4) in combination with a membrane-targeted enhanced green fluorescent protein reporter line provides a powerful genetic tool reproducibly to label SNa motoneuron projections and terminals at the periphery, and their dendritic tree in the ventral nerve cord. Thus, the highly restricted expression pattern of the B-H1/-H2 homeoproteins and notably the related Gal4 driver represent powerful genetic tools to identify and study genes that control axon guidance, synaptogenesis or dendritic arborization within a small subpopulation of motoneurons identifiable from embryogenesis to late larval stages.


Subject(s)
Dopamine/metabolism , Drosophila Proteins/biosynthesis , Drosophila/metabolism , Eye Proteins/biosynthesis , Motor Neurons/metabolism , Transcription Factors/biosynthesis , Animals , Axons/metabolism , Central Nervous System/embryology , Central Nervous System/growth & development , Central Nervous System/metabolism , Drosophila/embryology , Drosophila/growth & development , Drosophila Proteins/genetics , Embryo, Nonmammalian/metabolism , Eye Proteins/genetics , Homeodomain Proteins , Immunohistochemistry , Larva/metabolism , Transcription Factors/genetics
11.
Development ; 133(8): 1445-55, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16540509

ABSTRACT

During nervous system development, combinatorial codes of regulators act to specify different neuronal subclasses. However, within any given subclass, there exists a further refinement, apparent in Drosophila and C. elegans at single-cell resolution. The mechanisms that act to specify final and unique neuronal cell fates are still unclear. In the Drosophila embryo, one well-studied motoneuron subclass, the intersegmental motor nerve (ISN), consists of seven unique motoneurons. Specification of the ISN subclass is dependent upon both even-skipped (eve) and the zfh1 zinc-finger homeobox gene. We find that ISN motoneurons also express the GATA transcription factor Grain, and grn mutants display motor axon pathfinding defects. Although these three regulators are expressed by all ISN motoneurons, these genes act in an eve-->grn-->zfh1 genetic cascade unique to one of the ISN motoneurons, the aCC. Our results demonstrate that the specification of a unique neuron, within a given subclass, can be governed by a unique regulatory cascade of subclass determinants.


Subject(s)
Cell Differentiation/genetics , DNA-Binding Proteins/genetics , Drosophila Proteins/genetics , Drosophila/embryology , GATA Transcription Factors/genetics , Homeodomain Proteins/genetics , Motor Neurons/cytology , Repressor Proteins/genetics , Transcription Factors/genetics , Animals , Axons/metabolism , DNA-Binding Proteins/physiology , Drosophila/cytology , Drosophila/genetics , Drosophila Proteins/physiology , GATA Transcription Factors/physiology , Gene Expression Regulation, Developmental , Homeodomain Proteins/physiology , Interneurons/cytology , Interneurons/metabolism , Motor Neurons/metabolism , Receptors, Notch/physiology , Repressor Proteins/physiology , Signal Transduction/genetics , Transcription Factors/physiology
12.
Dev Biol ; 291(2): 253-63, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16458285

ABSTRACT

Motor neurons are defined by their axon projections, which exit the CNS to innervate somatic or visceral musculature, yet remarkably little is known about how motor axons are programmed to exit the CNS. Here, we describe the role of the Drosophila Zfh1 transcription factor in promoting axon exit from the CNS. Zfh1 is detected in all embryonic somatic motor neurons, glia associated with the CNS surface and motor axons, and one identified interneuron. In zfh1 mutants, ventral projecting motor axons often stall at the edge of the CNS, failing to enter the muscle field, despite having normal motor neuron identity. Conversely, ectopic Zfh1 induces a subset of interneurons--all normally expressing two or more "ventral motor neuron transcription factors" (e.g. Islet, Hb9, Nkx6, Lim3)--to project laterally and exit the CNS. We conclude that Zfh1 is required for ventral motor axon exit from the CNS.


Subject(s)
Axons/physiology , Brain/cytology , DNA-Binding Proteins/physiology , Drosophila Proteins/physiology , Motor Neurons/physiology , Repressor Proteins/physiology , Animals , Drosophila , Interneurons/physiology
13.
Neuron ; 35(5): 893-905, 2002 Aug 29.
Article in English | MEDLINE | ID: mdl-12372284

ABSTRACT

Target innervation by specific neuronal populations involves still incompletely understood interactions between central and peripheral factors. We show that glial cell line-derived neurotrophic factor (GDNF), initially characterized for its role as a survival factor, is present early in the plexus of the developing forelimb and later in two muscles: the cutaneus maximus and latissimus dorsi. In the absence of GDNF signaling, motor neurons that normally innervate these muscles are mispositioned within the spinal cord and muscle invasion by their axons is dramatically reduced. The ETS transcription factor PEA3 is normally expressed by these motor neurons and fails to be induced in most of them in GDNF signaling mutants. Thus, GDNF acts as a peripheral signal to induce PEA3 expression in specific motor neuron pools thereby regulating both cell body position and muscle innervation.


Subject(s)
Motor Neurons/physiology , Muscle, Skeletal/innervation , Nerve Growth Factors , Nerve Tissue Proteins/physiology , Transcription Factors/physiology , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , Embryo, Mammalian , Female , Glial Cell Line-Derived Neurotrophic Factor , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Motor Neurons/cytology , Muscle, Skeletal/cytology , Muscle, Skeletal/physiology , Nerve Tissue Proteins/biosynthesis , Organ Culture Techniques/methods , Signal Transduction/physiology
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