andre goffinet - Academia.edu (original) (raw)

Papers by andre goffinet

Journal of Biological Chemistry, 2003

Reelin is a large secreted signaling protein that binds to two members of the low density lipopro... more Reelin is a large secreted signaling protein that binds to two members of the low density lipoprotein receptor family, the apolipoprotein E receptor 2 and the very low density lipoprotein receptor, and regulates neuronal positioning during brain development. Reelin signaling requires activation of Src family kinases as well as tyrosine phosphorylation of the intracellular adaptor protein Disabled-1 (Dab1). This results in activation of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and the inhibition of glycogen synthase kinase 3␤, a protein that is implicated in the regulation of axonal transport. Here we demonstrate that PI3K activation by Reelin requires Src family kinase activity and depends on the Reelin-triggered interaction of Dab1 with the PI3K regulatory subunit p85␣. Because the Dab1 phosphotyrosine binding domain can interact simultaneously with membrane lipids and with the intracellular domains of apolipoprotein E receptor 2 and very low density lipoprotein receptor, Dab1 is preferentially recruited to the neuronal plasma membrane, where it is phosphorylated. Efficient Dab1 phosphorylation and activation of the Reelin signaling cascade is impaired by cholesterol depletion of the plasma membrane. Using a neuronal migration assay, we also show that PI3K signaling is required for the formation of a normal cortical plate, a step that is dependent upon Reelin signaling. The large signaling protein Reelin regulates the formation of a laminated neocortex in the developing brain (for reviews, see Refs.

Results and Problems in Cell Differentiation, 2000

Molecular and Cellular Biology, Oct 1, 2007

Reelin is an extracellular matrix protein with various functions during development and in the ma... more Reelin is an extracellular matrix protein with various functions during development and in the mature brain. It activates different signaling cascades in target cells, one of which is the phosphatidylinositol 3-kinase (PI3K) pathway, which we investigated further using pathway inhibitors and in vitro brain slice and neuronal cultures. We show that the mTor (mammalian target of rapamycin)-S6K1 (S6 kinase 1) pathway is activated by Reelin and that this depends on Dab1 (Disabled-1) phosphorylation and activation of PI3K and Akt (protein kinase B). PI3K and Akt are required for the effects of Reelin on the organization of the cortical plate, but their downstream partners mTor and glycogen synthase kinase 3␤ (GSK3␤) are not. On the other hand, mTor, but not GSK3␤, mediates the effects of Reelin on the growth and branching of dendrites of hippocampal neurons. In addition, PI3K fosters radial migration of cortical neurons through the intermediate zone, an effect that is independent of Reelin and Akt.

médecine/sciences, 1998

hez les animaux reeler, les neurones centraux sont engendrés au bon moment et en nombre normal. I... more hez les animaux reeler, les neurones centraux sont engendrés au bon moment et en nombre normal. Ils migrent initialement dans la bonne direction le long des fibres gliales radiaires mais, une fois arrivés à proximité de leur destination, ils ne parviennent pas à s'ordonner correctement. ADRESSES B. Bernier : ingénieur chimiste et des bio-industries, assistante. V. de Bergeyck : docteur ès sciences, chargée de recherches. C. Lambert de Rouvroit : docteur ès sciences, chargée de recherches. I. Royaux : docteur ès sciences, FRIA. A. M. Goffinet : docteur en médecine, docteur ès sciences.

médecine/sciences, 1996

Une des clés du développement est que les cellules dans l'organisme et les protéines dans les cel... more Une des clés du développement est que les cellules dans l'organisme et les protéines dans les cellules se trouvent à leur place normale. La mutation reeler perturbe typiquement la migration cellulaire, en l'occurrence celle des neurones corticaux qui ne s'arrêtent pas au cours de leur migration, dépassent leur position attitrée et se pressent au-delà, en périphérie de leur champ de migration. Le produit du gène reelin semble être une protéine de la matrice extracellulaire qui est sécrétée par des cellules ayant migré précocement en périphérie et forme un gradient répulsif essentiel à l'arrêt de la migration des neurones migrant ultérieurement. C'est aussi une interaction inhibitrice qui explique, dans l'embryon syncytial de drosophile, le gradient croissant de distribution antéro-postérieur de la protéine Caudal, dont le messager est distribué de façon homogène : sa traduction est inhibée par la protéine Bicoid, distribuée en gradient à partir d'un site de synthèse au pôle antérieur où se trouve concentré l'ARNm. Nous rapportons aussi un nouvel exemple de redondance fonctionnelle entre les membres d'une famille de protéines inductrices du développement, en l'occurrence les facteurs myogéniques de la famille MyoD : les protéines Myf5 et myogénine sont parfaitement interchangeables, la spécificité fonctionnelle de leurs gènes respectifs étant due à leurs différences d'expression spatiotemporelle. Ces résultats ont été obtenus par recombinaison homologue dans des cellules souches embryonnaires ES, méthode qui ne fonctionnait jusqu'alors que chez la souris. Mais, peut-être, d'autres espèces pourraient se prêter dans le futur à ces techniques, par exemple les brebis.

Development, 2017

The cerebral cortex covers the rostral part of the brain and, in higher mammals and particularly ... more The cerebral cortex covers the rostral part of the brain and, in higher mammals and particularly humans, plays a key role in cognition and consciousness. It is populated with neuronal cell bodies distributed in radially organized layers. Understanding the common and lineagespecific molecular mechanisms that orchestrate cortical development and evolution are key issues in neurobiology. During evolution, the cortex appeared in stem amniotes and evolved divergently in two main branches of the phylogenetic tree: the synapsids (which led to present day mammals) and the diapsids (reptiles and birds). Comparative studies in organisms that belong to those two branches have identified some common principles of cortical development and organization that are possibly inherited from stem amniotes and regulated by similar molecular mechanisms. These comparisons have also highlighted certain essential features of mammalian cortices that are absent or different in diapsids and that probably evolved after the synapsiddiapsid divergence. Chief among these is the size and multi-laminar organization of the mammalian cortex, and the propensity to increase its area by folding. Here, I review recent data on cortical neurogenesis, neuronal migration and cortical layer formation and folding in this evolutionary perspective, and highlight important unanswered questions for future investigation.

Proc Natl Acad Sci USA, 2014

Proceedings of the National Academy of Sciences, 2009

Apoptosis occurs widely during brain development, and p73 transcription factors are thought to pl... more Apoptosis occurs widely during brain development, and p73 transcription factors are thought to play essential roles in this process. The p73 transcription factors are present in two forms, the full length TAp73 and the N-terminally truncated DeltaNp73. In cultured sympathetic neurons, overexpression of DeltaNp73 inhibits apoptosis induced by nerve growth factor withdrawal or p53 overexpression. To probe the function of DeltaNp73 in vivo, we generated a null allele and inserted sequences encoding the recombinase Cre and green fluorescent protein (EGFP). We show that DeltaNp73 is heavily expressed in the thalamic eminence (TE) that contributes neurons to ventral forebrain, in vomeronasal neurons, Cajal-Retzius cells (CRc), and choroid plexuses. In DeltaNp73 −/− mice, cells in preoptic areas, vomeronasal neurons, GnRH-positive cells, and CRc were severely reduced in number, and choroid plexuses were atrophic. This phenotype was enhanced when DeltaNp73–positive cells were ablated by dip...

Nature Communications, 2016

The diaphanous homologue Diaph3 (aka mDia2) is a major regulator of actin cytoskeleton. Loss of D... more The diaphanous homologue Diaph3 (aka mDia2) is a major regulator of actin cytoskeleton. Loss of Diaph3 has been constantly associated with cytokinesis failure ascribed to impaired accumulation of actin in the cleavage furrow. Here we report that Diaph3 is required before cell fission, to ensure the accurate segregation of chromosomes. Inactivation of the Diaph3 gene causes a massive loss of cortical progenitor cells, with subsequent depletion of intermediate progenitors and neurons, and results in microcephaly. In embryonic brain extracts, Diaph3 co-immunoprecipitates with BubR1, a key regulator of the spindle assembly checkpoint (SAC). Diaph3-deficient cortical progenitors have decreased levels of BubR1 and fail to properly activate the SAC. Hence, they bypass mitotic arrest and embark on anaphase in spite of incorrect chromosome segregation, generating aneuploidy. Our data identify Diaph3 as a major guard of cortical progenitors, unravel novel functions of Diaphanous formins and add insights into the pathobiology of microcephaly.

The International Journal of Biochemistry & Cell Biology, 2015

The assembly of functional neuronal circuits depends on the correct wiring of axons and dendrites... more The assembly of functional neuronal circuits depends on the correct wiring of axons and dendrites. To reach their targets, axons are guided by a variety of extracellular guidance cues, including Netrins, Ephrins, Semaphorins and Slits. Corresponding receptors in the growth cone, the dynamic structure at the tip of the growing axon, sense and integrate these positional signals, and activate downstream effectors to regulate cytoskeletal organization. In addition to the four canonical families of axon guidance cues mentioned above, some proteins that regulate planar cell polarity were recently found to be critical for axon guidance. The seven-transmembrane domain receptors Celsr3 and Fzd3, in particular, control the development of most longitudinal tracts in the central nervous system, and axon navigation in the peripheral, sympathetic and enteric nervous systems. Despite their unequivocally important role, however, underlying molecular mechanisms remain elusive. We do not know which extracellular ligands they recognize, whether they have co-receptors in the growth cone, and what their downstream effectors are. Here, we review some recent advances and discuss future trends in this emerging field.

Zeitschrift für mikroskopisch-anatomische Forschung, 1984

Analyse de l'histogenese du cortex cerebral de quelques reptiles et comparaison avec le devel... more Analyse de l'histogenese du cortex cerebral de quelques reptiles et comparaison avec le developpement cortical des mammiferes

Acta neurologica Belgica

Noradrenaline (NA) exerts its physiological and pharmacological effects in the central nervous sy... more Noradrenaline (NA) exerts its physiological and pharmacological effects in the central nervous system by interacting with specific receptor sites which are divided into four subtypes, namely alpha-1, alpha-2, beta-1 and beta-2 adrenoceptors. Alpha-1 and beta-1 receptors are thought to be neuronal and post-synaptic, whereas alpha-2-R are neuronal pre- and postsynaptic and beta-2-R have a non neuronal (glial, vascular) localization. The autoradiographic localization of adrenergic receptors is requisite to a better understanding of adrenergic modulation in the nervous system. It complements analyses of adrenergic fibers and terminals and allows comparisons between afferent transmission and various receptor systems. In addition, receptor autoradiography is a preliminary step towards non invasive, in vivo receptor imaging using positron emission tomography (PET). Classical autoradiographic methods using tritium-labeled ligands are relatively tedious, as they require exposure times of sev...

Aviation, space, and environmental medicine, 1990

Brain glucose metabolism was studied, using positron emission tomography and [F-18]-2-deoxy-2-flu... more Brain glucose metabolism was studied, using positron emission tomography and [F-18]-2-deoxy-2-fluoro-D-glucose, in 13 healthy young adult men, at rest and under conditions of high visual and auditory stimulation with minor motor involvement. Despite high individual variations, the mean cerebral metabolic rate for glucose was highly increased during stimulation. Furthermore, the regional pattern of cerebral glucose utilization showed consistent differences between resting and activated states. Several brain areas, including temporal, motor-premotor and parieto-occipital cortices, and striatum, thalamus, and cerebellum showed a level of activation statistically comparable to that of mean gray. Significant preferential activation was found only in the visual cortex. By contrast, prefrontal and mesial cortical areas were relatively hypoactivated by the task. Inasmuch as prefrontal cortex is known to receive visual associative afferents, these observations are tentatively interpreted in ...

Mammalian Genome, 1991

The location of the reeler (rI) locus in mice in the paracentromeric part of chromosome (Chr) 5, ... more The location of the reeler (rI) locus in mice in the paracentromeric part of chromosome (Chr) 5, proximal to the T(5;12)31H translocation breakpoint, has been confirmed. Analysis of DNA from animals with different doses of the proximal part of Chr 5 and from congenic mice showed that the Pgy-1 locus is the closest marker to rl, whereas En-2 is located farther, distal to the T31H breakpoint. Together with recently published evidence (Martin et al. 1989), our data suggest the following order: Cen-rl/Pgy-l-T31H-En-2.

The Journal of Comparative Neurology, 1998

Reelin, the protein defective in reeler mutant mice, is a secreted glycoprotein involved in the a... more Reelin, the protein defective in reeler mutant mice, is a secreted glycoprotein involved in the architectonic development of the central nervous system, more particularly in the development of neocortical lamination. In mice, reelin mRNA and protein expression are most robust in horizontal neurons of the embryonic marginal zone (MZ). By using monoclonal anti-reelin antibodies (de Bergeyck et al. [1998] J. Neurosci. Methods), the morphology and evolution of reelin-expressing neurons were studied in the MZ of the prenatal human neocortex. At 11 gestational weeks (GW), the MZ contained a single layer of reelin-positive mono- or bipolar horizontal Cajal-Retzius (CR) cells. From 14 GW onward, the subpial granular layer (SGL) invaded the MZ, forming a transient layer of undifferentiated, initially reelin-negative granule cells. In parallel to the emergence of the SGL and the morphological differentiation of the CR cells, a second population of reelin-positive cells appeared within the SGL. These cells, termed CR-like cells, were intermediate in size and shape between the CR cells and SGL granule cells. Between 16 GW and 24 GW, the packing density of the reelin-producing cells remained remarkably stable, despite the continuous growth of the cortical surface. During this period, CR cells settled progressively deeper within the MZ, although they remained in contact with the pial surface through radially ascending processes. Most CR cells disappeared at around 27 GW, in parallel with the dissolution of the SGL. During the last weeks of gestation, reelin was expressed by a few medium-sized, often horizontal neurons. These observations show that different neuronal populations in the human MZ express reelin and suggest that a possible function of the SGL is to supply reelin-producing cells through a gradual transformation of reelin-negative precursor cells into reelin-immunoreactive CR-like cells, thus coping with the protracted neurogenesis and dramatic surface expansion of the human neocortex.

Genomics, 1995

The reeler mutation in the mouse maps to proximal chromosome 5 and defines a key gene involved in... more The reeler mutation in the mouse maps to proximal chromosome 5 and defines a key gene involved in brain development and evolution. No gene product is known, and the locus is currently being characterized by positional cloning. YAC clones corresponding to the closest markers &I&fit61 and D5iWt72 have been isolated. Cloned extremities of the YAC inserts were used to construct a 1.1.Mb contig, a 700.kb fragment of which was shown to contain the reeler locus. The integrity of the contig was verified by physical mapping on genomic DNA. The classical allele of the reeler mutation was associated with a 150.kb deletion between D52Mit61 and D5Mit72, while no gross chromosomal anomaly was found in the Orleans allele. Candidate coding sequences were isolated to construct a preliminary transcriptional map of the reeler region. Cosmid clones mapping within the rl deletion revealed a large transcript of more than 11 kb, which was present in normal embryonic brain but barely detectable in homoxygous rP1lrZorl embryonic brain, suggesting strongly that it corresponds to the reeler transcript. D 1~15

Cell and Tissue Research, 1981

Inverted pyramidal neurons are very abundant in the cerebral cortex of the adult reeler mutant mo... more Inverted pyramidal neurons are very abundant in the cerebral cortex of the adult reeler mutant mouse. Two types of inverted pyramid are found in rapid Golgi impregnations. In the first type the axon starts from the base of the cell body and bends towards the white matter. In the second type, which is more common, the axon emerges from the apical dendritic tree and descends directly towards the white matter. Despite its abnormal topography, the site of origin of the axon in pyramids of the second type displays a normal differentiation, when analysed with the electron microscopic Golgi technique, suggesting that the ectopic initial axon segment is able to fulfil its normal functions.

Brain Research, 1985

The distribution of a 1-and flradrenoceptors has been examined in the ferret visual cortex (area ... more The distribution of a 1-and flradrenoceptors has been examined in the ferret visual cortex (area 17), with an autoradiographic procedure using iodine-125 labeled hydroxy-iodophenyl-ethylaminomethyl-tetralone (HEAT) and iodocyanopindolol (ICYP), respectively. The density of ligand binding with ICYP, known to have selective affinity for fl-receptors, was heavy over layers I-III, very low over layer IV, and medium over V and VI. In contrast, binding sites for HEAT, a new ligand selective for a-receptors, were diffusely distributed, although preferentially concentrated in layer IV and the upper layers. The distinct laminar distribution of these two receptor types may imply two cortical channels for norepinephrine influence; al-receptors may be preferentially associated with enhancement of excitatory inputs to layer IV; ill-receptors, in contrast, with enhancement of inhibitory responses outside layer IV.