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The precerebellar system provides an interesting model to study tangential migrations. All precerebellar neurons (PCN) are generated in the most alar part of the hindbrain in a region called rhombic lip. PCN first emit a leading process and then translocate their nuclei inside it, a mechanism called nucleokinesis. In the past few years, molecular cues that could affect those processes have been investigated, with a special care on: (i) the identification of extrinsic factors directing cell migration and axon elongation as well as neuronal survival during development; (ii) intracellular reorganizations of the cytoskeleton during nucleokinesis in response to chemotropic factors. The signaling cascades, including regulators of actin and microtubule cytoskeleton, in response to diffusible guidance factors have raised an increasing attention. We will here review the role of guidance cues involved in PCN migration in particular netrin-1, Slit and Nr-CAM. We will also consider Rho-GTPases that have been proposed to mediate axon outgrowth and neuronal migration, especially in response to netrin-1, and which may act as a relay between extracellular signals and intracellular remodeling. Recent findings from in vitro pharmacological inhibition of various Rho-GTPases and over-expression of effectors bring molecular cues that, in accordance with anatomical data, fit the idea that nucleokinesis and axon outgrowth are not strictly coupled events during PCN migration.

Recent human genetics approaches identified the Aristaless-related homeobox (ARX) gene as the causative gene in X-linked infantile spasms, Partington syndrome, and non-syndromic mental retardation as well as in forms of lissencephaly with abnormal genitalia. The ARX predicted protein belongs to a large family of homeoproteins and is characterised by a C-terminal Aristaless domain and an octapeptide domain near the N-terminus. In order to learn more about ARX function, we have studied in detail Arx expression in the central nervous system during mouse embryonic development as well as in the adult. During early stages of development, Arx is expressed in a significant proportion of neurons in the cortex, the striatum, the ganglionic eminences and also in the spinal cord. In the adult, expression of Arx is still present and restricted to regions that are known to be rich in GABAergic neurons such as the amygdala and the olfactory bulb. A possible role for Arx in this type of neurons is further reinforced by the expression of Arx in a subset of GABAergic interneurons in young and mature primary cultures of cortical neuronal cells as well as in vivo. Moreover, these data could explain the occurrence of seizures in the great majority of patients with an ARX mutation, due to mislocalisation or dysfunction of GABAergic neurons. We also performed ARX wild-type and mutant over-expression experiments and found that the different ARX mutations tested did not modify the morphology of the cells. Moreover, no abnormal cell death or protein aggregation was observed, hence suggesting that more subtle pathogenic mechanisms are involved.

L’empreinte parentale est un phenomene epigenetique complexe qui regule l’expression monoallelique de certains genes en fonction de l’origine parentale de l’allele. Les genes soumis a empreinte (GSE) participent au developpement placentaire et fœtal. Des defauts d’empreinte de certains GSE entrainent des syndromes cliniques associant une pathologie placentaire a l’origine notamment d’un defaut de croissance fœtale, et des manifestations neuro-developpementales. Environ 70 GSE ont ete identifies a ce jour chez l’homme. Nous avons developpe une strategie de criblage haut debit pour identifier de nouveaux GSE dans le placenta humain. Une premiere serie de validation a permis de confirmer le statut d’empreinte d’une dizaine de nouveaux genes [1] . Recemment, nous avons revele le statut de GSE pour le gene DSCAM (Down Syndrome Cellular Adhesion Molecule). Ce gene, qui se trouve dans la region critique du syndrome de Down, est ainsi le premier GSE identifie sur le chromosome 21. Notre etude montre que c’est l’allele paternel qui est exprime dans le placenta. Des resultats preliminaires nous laissent penser que l’empreinte de ce gene pourrait etre regulee par une region differentiellement methylee en amont du gene. L’etude par immunohistochimie de coupes placentaires montre une expression dans les cellules endotheliales et le syncytiotrophoblaste pouvant suggerer un role dans l’angiogenese placentaire via son ligand Netrin. Une etude est en cours a partir d’un modele cellulaire de trophoblaste avant et apres syncytialisation pour analyser son role dans ce type cellulaire. Par ailleurs, DSCAM est connu pour son role dans la mise en place des connections inter-neurones [2] . Une etude est en cours sur des modeles murins afin d’analyser le statut d’empreinte de ce gene dans le tissu nerveux et les consequences d’un defaut d’expression de son ligand Netrin sur le developpement placentaire.