[Development and maintenance of the neuromuscular system].

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.

Onset of Spinal Cord Astrocyte Precursor Emigration from the Ventricular Zone Involves the Zeb1 Transcription Factor.

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.

Zeb family members and boundary cap cells underlie developmental plasticity of sensory nociceptive neurons.

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).

Eph:ephrin-B1 forward signaling controls fasciculation of sensory and motor axons.

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.

Coe genes are expressed in differentiating neurons in the central nervous system of protostomes.

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.

Low-threshold mechanoreceptor subtypes selectively express MafA and are specified by Ret signaling.

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.

A mesenchymal-like ZEB1(+) niche harbors dorsal radial glial fibrillary acidic protein-positive stem cells in the spinal cord.

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.

Zfh1 promotes survival of a peripheral glia subtype by antagonizing a Jun N-terminal kinase-dependent apoptotic pathway.

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.

A SAGE-based screen for genes expressed in sub-populations of neurons in the mouse dorsal root ganglion.

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.

Expression of Drosophila BarH1-H2 homeoproteins in developing dopaminergic cells and segmental nerve a (SNa) motoneurons.

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.

Specification of Drosophila aCC motoneuron identity by a genetic cascade involving even-skipped, grain and zfh1.

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.

Zfh1, a somatic motor neuron transcription factor, regulates axon exit from the CNS.

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.

GDNF acts through PEA3 to regulate cell body positioning and muscle innervation of specific motor neuron pools.

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.