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Biomedical subjects

A M Goffinet

Publications and source records attributed to A M Goffinet.

At least 19 recordsLinked to original sources
PubMed2002

Developmental expression profiles of Celsr (Flamingo) genes in the mouse.

Celsr, also called Flamingo (Fmi) genes encode proteins of the cadherin superfamily. Celsr cadherins are seven-pass transmembrane proteins with nine cadherin repeats in the extracellular domain, and an anonymous intracellular C-terminus. The Drosophila Fmi gene regulates epithelial planar cell polarity and dendritic field deployment. The three Flamingo gene orthologs in man and rodents are named, respectively, CELSR1-3 and Celsr1-3. Celsr1 and 2 are expressed during early development, in the brain and epithelia. In this report, we characterized further Celsr genes in the mouse, and examined their developmental pattern of expression. Each Celsr is expressed prominently in the developing brain following a specific pattern, suggesting that they serve distinct functions.

Animals↗
PubMed2001

Reelin does not directly influence axonal growth.

Reelin is a large extracellular glycoprotein involved in the development of architectonic patterns, particularly in the cerebral cortex and hippocampus, where it is synthesized primarily by Cajal-Retzius cells. In the hippocampus, Reelin also regulates the growth and/or distribution of afferent entorhinal and commissural axons. To assess further the possible action of Reelin on axonal growth, we used the three-dimensional collagen gel assay to measure axonal elongation from reeler cortical explants in the presence of Reelin. Because Reelin is proteolytically processed in vivo, normal explants and Reelin-transfected human embryonic kidney 293T cells were used, respectively, as sources of processed and full-length protein. The reliability of the assay was tested by demonstrating a clear repulsive action of semaphorin 3F (p < 0.0001). However, neither full-length nor processed Reelin exhibited any significant attraction or repulsion on cortical axons. Our results suggest that the reported effects of Reelin on axonal pathways are indirect, secondary to the architectonic disturbances that result from Reelin deficiency, and that the effects of Cajal-Retzius cells on connectivity are primarily independent of Reelin.

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PubMed2001

Tbr1 regulates differentiation of the preplate and layer 6.

During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.

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PubMed2001

Neuronal migration.

Like other motile cells, neurons migrate in three schematic steps, namely leading edge extension, nuclear translocation or nucleokinesis, and retraction of the trailing process. In addition, neurons are ordered into architectonic patterns at the end of migration. Leading edge extension can proceed at the extremity of the axon, by growth cone formation, or from the dendrites, by formation of dendritic tips. Among both categories of leading edges, variation seems to be related to the rate of extension of the leading process. Leading edge extension is directed by microfilament polymerization following integration of extracellular cues and is regulated by Rho-type small GTPases. In humans, mutations of filamin, an actin-associated protein, result in heterotopic neurons, probably due to defective leading edge extension. The second event in neuron migration is nucleokinesis, a process which is critically dependent on the microtubule network, as shown in many cell types, from slime molds to vertebrates. In humans, mutations in the PAFAH1B1 gene (more commonly called LIS1) or in the doublecortin (DCX) gene result in type 1 lissencephalies that are most probably due to defective nucleokinesis. Both the Lis1 and doublecortin proteins interact with microtubules, and two Lis1-interacting proteins, Nudel and mammalian NudE, are components of the dynein motor complex and of microtubule organizing centers. In mice, mutations of Cdk5 or of its activators p35 and p39 result in a migration phenotype compatible with defective nucleokinesis, although an effect on leading edge formation is also likely. The formation of architectonic patterns at the end of migration requires the integrity of the Reelin signalling pathway. Other known components of the pathway include members of the lipoprotein receptor family, the intracellular adaptor Dab1, and possibly integrin alpha 3 beta 1. Defective Reelin leads to poor lamination and, in humans, to a lissencephaly phenotype different from type 1 lissencephaly. Although the action of Reelin is unknown, it may trigger some recognition-adhesion among target neurons. Finally, pattern formation requires the integrity of the external limiting membrane, defects of which lead to overmigration of neurons in meninges and to human type 2 lissencephaly.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

Reelin mRNA expression during embryonic brain development in the chick.

The expression of reelin mRNA was studied during embryonic brain development in the chick, by using in situ hybridization. Reelin was highly expressed in the olfactory bulb and in subpial neurons in the marginal zone of the cerebral cortex. In the diencephalon, the ventral division of lateral geniculate nuclei and perirotundal nuclei were strongly positive. High levels of expression were associated with some layers of the tectum and with the external granule cell layer of the cerebellum. A more moderate signal was detected in the septal nuclei, hyperstriatal fields, retina, habenular nuclei and hypothalamus, in some reticular nuclei of the mid- and hindbrain, and in the spinal cord. Little or no expression was observed in the cortical plate, Purkinje cells, or the inferior olivary complex. Comparison with reelin expression during mammalian and reptilian brain development reveals several evolutionarily conserved features that presumably define a homology. In addition, significant differences are noted, particularly in telencephalic fields. Most importantly, the developing chick cortex does not exhibit high levels of reelin expression in subpial Cajal-Retzius cells characteristic of the mammalian brain. These observations are compatible with an action of reelin on adhesion and/or of nucleokinesis at the level of target cells. They further suggest that, whereas the telencephalon of birds and archosaurs evolved primarily from dorsal ventricular ridge derivatives in which reelin is probably secondary, the increase in number of reelin-positive cells, and amplification of reelin expression played a key part in the evolution of the cortex in the synapsid lineage leading to mammals.

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PubMed2000

Embryonic and early fetal development of the human neocortex.

Early corticogenesis was studied in human embryos and early fetuses from Carnegie stages 16 to 22 (5-8 gestational weeks) by using immunohistochemistry for Reelin (Reln), calretinin (CR), and glutamic acid decarboxylase (GAD). A first population of Reln-positive cells appears in the neocortical anlage at stage 16 and increases in number at stages 17-18. At stages 19-20, a monolayer of horizontal CR- and GAD-positive, Reln-negative neurons forms in the preplate, whereas Reln-positive cells shift into a subpial position. Another cell class, the pioneer projection neuron, is CR-positive but GAD- and Reln-negative; pioneer cells contribute early corticofugal axons. Pioneer cells first appear below the monolayer at stage 20 and form a pioneer plate at stage 21. The cortical plate (CP) proper emerges at stage 21 and inserts itself within the pioneer plate, which is thus split into a minor superficial component and a larger deep component that presumably corresponds to the subplate. Initial CP neurons are radially organized and mostly CR-negative. Reln-positive cells remain consistently segregated from the pioneer cells and are thus not directly involved in preplate partition. Our data indicate that the neuronal composition of the human neocortical preplate is more complex than generally described and that various neurons participate in a sequence of events that precede the emergence of the CP.

Calbindin 2↗
PubMed2000

Evolution of cortical lamination: the reelin/Dab1 pathway.

The mammalian cortical plate is characterized by its radial organization and its inside-outside developmental gradient. Observations on reelin and Dab1-deficient mice show that reelin and Dab1 are both required to develop radial cortical organization and a normal maturation gradient. In the reptilian cortex, radial organization varies among species; it is the most rudimentary in turtles and the most elaborate in lizards, and can be described as intermediate in other species such as crocodilians and Sphenodon. On the other hand, the gradient of corticogenesis is directed from outside to inside in all reptiles studied, as well as in mice that are deficient in reelin, Dab1, as well as cyclin-dependent kinase 5 (Cdk5) and p35. All reptiles, even turtles, have reelin-expressing cells in the embryonic marginal zone. Mammals are characterized by a drastic increase in the number of reelin-positive cells (Cajal-Retzius cells) as well as by an amplification of reelin expression per cell. In lizards, the pattern of reelin expression is different, as reelin-expressing cells are also present below the cortical plate. In all mammalian and reptilian species, Dab1 is expressed in cortical plate cells. These data suggest that the reelin/Dab1 pathway was a driver of cortical evolution on the synapsid lineage and that similarities in radial cortical organization between squamates and mammals result from evolutionary convergence.

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PubMed2000

The evolution of cortical development. An hypothesis based on the role of the Reelin signaling pathway.

Expression of the genes encoding Reelin and Dab1 during cortical development in turtle, lizard, chick and mammals correlates with architectonic patterns. In all species, Reelin is secreted by marginal zone cells, whereas Dab1, which mediates the response to Reelin, is synthesized by cortical plate neurons. This pattern was presumably present in stem amniotes. In mammals, the cortical plate is radially organized and develops from inside to outside, these features depend on amplification of reelin synthesis in the marginal zone. In lizards, the cortical plate develops from outside to inside, similar to other non-mammals, but is radially organized, with an additional layer of Reelin added in the subcortex. Thus, the Reelin pathway played a key role in cortical architectonic evolution in mammalian and squamate lineages.

Animals↗
PubMed2000

Potential mechanisms of mutations that affect neuronal migration in man and mouse.

Mutations in the genes that encode filamin-1, Lis1 and doublecortin are responsible for X-linked lissencephaly in man, whereas mutations in the genes that encode Cdk5, its activator p35 and the reelin-signaling pathway disturb migration and architectonic development in mice. To understand the action of genes that control neuronal migration and the phenotype of corresponding defects, it might be as important to consider the positioning of the nucleus as it is to consider the guidance of the leading process.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

The Reelin signaling pathway in mouse cortical development.

Most of the cerebral cortex derives from the cortical plate which, in all mammals, is radially organized and develops from inside to outside. Several genes involved in the organization and inside-outside development of the embryonic cortical plate in the mouse form the so-called Reelin signaling pathway. Biochemical and genetic arguments show that the extracellular matrix protein Reelin binds to two lipoprotein receptors (VLDLR and ApoER2), which relay the Reelin signal inside target neurons by docking the tyrosine kinase adapter disabled-1 (Dab1). In addition, biochemical evidence suggests that the integrins alpha 3/beta 1 and protocadherins of the CNR family may also modulate the Reelin signal. The mechanisms by which the presence of Reelin stops migration and instructs the radial organization of cortical plate cells remains unknown.

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PubMed1999

Reelin expression during embryonic brain development in lacertilian lizards.

The expression of reelin mRNA and protein was studied during embryonic brain development in the lacertilian lizards L. viridis and L. galloti, by using radioactive in situ hybridization and immunohistochemistry. At all stages studied, high reelin expression was consistently found in the olfactory bulb, in the lateral cortex, and in neurons of the marginal zone and subplate of medial and dorsal cortical sectors. In the dorsal ventricular ridge (DVR), reelin expression was confined to deeply located, large cells which were more abundant in the caudal than the rostral part of the DVR. In the diencephalon, the ventral lateral geniculate complex and the perirotundal were strongly positive, whereas other nuclei were mostly negative. High reelin signal was associated with some layers in the tectum, with the torus semicircularis, cerebellar granule cell layers, and the ventral horn of the spinal cord. A more moderate signal was detected in the septal nuclei, striatum, retina, habenular nuclei, preoptic and periventricular hypothalamic components, and in reticular nuclei of the mid- and hindbrain. The medial and dorsal cortical plate and Purkinje cells were reelin-negative but expressed disabled-1 (Dab1) mRNA. When they are compared with reelin expression during mammalian brain development, our data reveal an evolutionarily conserved canvas of reelin expression, as well as significant differences, particularly in developing cortical fields. The developing lizard cortex differs from that of turtles, birds, crocodiles, and mammals in that it displays heavy reelin expression not only in neurons of the marginal zone that might be homologous to mammalian Cajal-Retzius cells, but also in subplate neurons. This difference in the pattern of reelin expression suggests that the elaborate radial organization of the lacertilian cortical plate, somewhat reminiscent of its mammalian counterpart, results from evolutionary convergence. Our data lend support to the hypothesis that the reelin signaling pathway played a significant role during cortical evolution.

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PubMed1999

Reelin mRNA expression during embryonic brain development in the turtle Emys orbicularis.

The expression of reelin messenger ribonucleic acid (mRNA) was studied during embryonic brain development in the turtle Emys orbicularis, by using radioactive in situ hybridization. A high expression was consistently found in the olfactory bulb and in a few neurons in the marginal zone and, to a lesser extent, in the subplate of the dorsal and medial cortical sectors. In the diencephalon, the ventral division of lateral geniculate nuclei and the prospective reticular thalamic nuclei were strongly positive. High reelin signal was also associated with some layers of the tectum and with the external granule cell layer of the cerebellum. A more moderate signal was detected in the septal nuclei, striatum, dorsal ventricular ridge, retina, habenular nuclei, and hypothalamus, and in some reticular nuclei of the midbrain and hindbrain and in ventral spinal cord. The cortical plate, basal forebrain, amygdala, and tegmentum were weakly labeled. When they are compared to reelin expression during mammalian brain development, our data reveal an evolutionarily conserved canvas of reelin expression and significant differences, particularly in developing cortical fields. Most significantly, the developing turtle cortex does not display the heavy reelin expression in subpial Cajal-Retzius cells that is so typical of its mammalian counterpart. Given the key role of reelin in laminar cortical development, our data suggest that the increase in the number of reelin-producing cells and/or the amplification of reelin expression in the cortical marginal zone might have been a driving factor during the evolution of the laminated cerebral cortex from stem reptiles to mammals, as indicated in previous comparative analyses.

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PubMed1999

Reelin, the extracellular matrix protein deficient in reeler mutant mice, is processed by a metalloproteinase.

Reelin is the extracellular protein defective in reeler mice. It is believed that reelin acts via the extracellular matrix to influence the development of nearby neurons, but the mechanism remains thus far unknown. In the present work, we present in vivo and in vitro evidence that reelin is cleaved. This processing did not occur in Relnrl-Orl mutant mice in which reelin is not secreted and was prevented in explant cultures by brefeldin treatment, suggesting that it takes place extracellularly or in a postendoplasmic reticulum compartment. Reelin cleavage was inhibited by zinc chelators known to inhibit metalloproteinases but was unaffected by inhibitors of serine, cysteine, or aspartate proteinases. Furthermore, reelin cleavage was insensitive to inhibitors of matrixins, neprilysin, meprin, and peptidyl dipeptidase A, suggesting that the processing enzyme belongs to a different enzyme family. This enzyme and the physiological meaning of reelin processing remain to be characterized further.

Animals↗
PubMed1999

Evolutionarily conserved, alternative splicing of reelin during brain development.

Reelin is the protein defective in reeler mutant mice and plays a pivotal role in brain development. However, some uncertainties remain about the relationship between reelin and the reeler phenotype. It is generally believed that reelin, secreted by specific neuronal types such as Cajal-Retzius cells, acts at short distance via the extracellular matrix on target neurons, the response of which requires the Dab1 gene product. However, the pattern of reelin expression in some structures such as olfactory bulb, retina, and spinal cord suggests that the protein might be endowed with different functions. In the present study, we identify two uncommon, evolutionarily conserved splicing events in the 3' part of the transcript that result in different forms of the protein. First, a 6-nucleotide, brain-specific microexon is skipped in about 10% of reelin RNA. In addition, an alternative polyadenylation event involving 10-25% of reelin mRNA results in secretion of a truncated protein lacking the terminal, highly basic stretch. This alternative reelin is generally expressed in the same cells as the major form, but is almost undetectable in retina and spinal cord. Both alternative splicing events are present in mouse, rat, and man, suggesting that the corresponding reelin forms are functionally important.

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PubMed1998

A new view of early cortical development.

Recently, several genes that regulate the development of the cerebral cortex and are potential pharmacological targets have been cloned. Reelin, an extracellular matrix glycoprotein secreted by Cajal-Retzius cells in the marginal zone, instructs the radial organization of the cortical plate. The response of cortical plate cells to reelin requires the tyrosine kinase adaptor disabled-1 (Dab1). Cyclin-dependent kinase 5 and its activator p35 are necessary for the development of the cortical plate, probably at a later stage than reelin/Dab1. The transcription factor Tbr-1 is essential for differentiation of preplate and Cajal-Retzius cells and for formation of thalamocortical connections, while D1x-1/2 are required for tangential migration. Some neurotrophin systems such as neurotrophin 4, brain-derived neurotrophic factor, and neuregulin and its receptor ErbB are also thought to assist in the regulation of cortical development. In addition, a few genes implicated in human cortical dysplasias have been characterized. LIS1 encodes a protein related to platelet-activating factor acetyl hydrolase that is defective in lissencephaly-1 of the Miller-Dieker type, while the double cortex malformation is related to mutations of a new gene dubbed doublecortn.

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