RESUMEN
Normal central nervous system development relies on accurate intrinsic cellular programs as well as on extrinsic informative cues provided by extracellular molecules. Migration of neuronal progenitors from defined proliferative zones to their final location is a key event during embryonic and postnatal development. Extracellular matrix components play important roles in these processes, and interactions between neurons and extracellular matrix are fundamental for the normal development of the central nervous system. Guidance cues are provided by extracellular factors that orient neuronal migration. During cerebellar development, the extracellular matrix molecules laminin and fibronectin give support to neuronal precursor migration, while other molecules such as reelin, tenascin, and netrin orient their migration. Reelin and tenascin are extracellular matrix components that attract or repel neuronal precursors and axons during development through interaction with membrane receptors, and netrin associates with laminin and heparan sulfate proteoglycans, and binds to the extracellular matrix receptor integrins present on the neuronal surface. Altogether, the dynamic changes in the composition and distribution of extracellular matrix components provide external cues that direct neurons leaving their birthplaces to reach their correct final location. Understanding the molecular mechanisms that orient neurons to reach precisely their final location during development is fundamental to understand how neuronal misplacement leads to neurological diseases and eventually to find ways to treat them.
Asunto(s)
Humanos , Movimiento Celular/fisiología , Cerebelo/embriología , Proteínas de la Matriz Extracelular/fisiología , Matriz Extracelular/fisiología , Neuronas/fisiología , Moléculas de Adhesión Celular Neuronal/fisiología , Proteínas del Tejido Nervioso/fisiología , Transducción de Señal/fisiologíaRESUMEN
Normal central nervous system development relies on accurate intrinsic cellular programs as well as on extrinsic informative cues provided by extracellular molecules. Migration of neuronal progenitors from defined proliferative zones to their final location is a key event during embryonic and postnatal development. Extracellular matrix components play important roles in these processes, and interactions between neurons and extracellular matrix are fundamental for the normal development of the central nervous system. Guidance cues are provided by extracellular factors that orient neuronal migration. During cerebellar development, the extracellular matrix molecules laminin and fibronectin give support to neuronal precursor migration, while other molecules such as reelin, tenascin, and netrin orient their migration. Reelin and tenascin are extracellular matrix components that attract or repel neuronal precursors and axons during development through interaction with membrane receptors, and netrin associates with laminin and heparan sulfate proteoglycans, and binds to the extracellular matrix receptor integrins present on the neuronal surface. Altogether, the dynamic changes in the composition and distribution of extracellular matrix components provide external cues that direct neurons leaving their birthplaces to reach their correct final location. Understanding the molecular mechanisms that orient neurons to reach precisely their final location during development is fundamental to understand how neuronal misplacement leads to neurological diseases and eventually to find ways to treat them.
Asunto(s)
Movimiento Celular/fisiología , Cerebelo/embriología , Proteínas de la Matriz Extracelular/fisiología , Matriz Extracelular/fisiología , Neuronas/fisiología , Moléculas de Adhesión Celular Neuronal/fisiología , Humanos , Proteínas del Tejido Nervioso/fisiología , Proteína Reelina , Transducción de Señal/fisiologíaRESUMEN
The roughest locus of Drosophila melanogaster encodes a transmembrane protein of the immunoglobulin superfamily required for several developmental processes, including axonal pathfinding in the developing optic lobe, mechanosensory bristle differentiation and myogenesis. In the compound eye, rst was previously shown to be required for establishing the correct number and spacing of secondary and tertiary pigment cells during the final steps of ommatidial assembly. We have further investigated its function in the developing pupal retina by performing a developmental and molecular analysis of a novel dominant rst allele, rst(D). In addition to showing evidence that rst(D) is a regulatory mutant, the results strongly suggest a previously unnoticed role of the rst gene in the differentiation of secondary/tertiary pigment cell fate as well as establishing the correct timing of surplus cell removal by programmed cell death in the compound eye.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/embriología , Drosophila melanogaster/genética , Proteínas del Ojo/fisiología , Regulación del Desarrollo de la Expresión Génica , Células Fotorreceptoras de Invertebrados/embriología , Naranja de Acridina/farmacología , Actinas/metabolismo , Alelos , Animales , Apoptosis , Southern Blotting , Moléculas de Adhesión Celular Neuronal/genética , Diferenciación Celular , Proteínas de Drosophila/genética , Proteínas del Ojo/genética , Inmunohistoquímica , Modelos Genéticos , Mutación , Faloidina/farmacología , Fenotipo , Pupa/metabolismo , Factores de Tiempo , Transcripción GenéticaRESUMEN
This article proposes a comprehensive view of the origin of the mammalian brain. We discuss i) from which region in the brain of a reptilian-like ancestor did the isocortex originate, and ii) the origin of the multilayered structure of the isocortex from a simple-layered structure like that observed in the cortex of present-day reptiles. Regarding question i there have been two alternative hypotheses, one suggesting that most or all the isocortex originated from the dorsal pallium, and the other suggesting that part of the isocortex originated from a ventral pallial component. The latter implies that a massive tangential migration of cells from the ventral pallium to the dorsal pallium takes place in isocortical development, something that has not been shown. Question ii refers to the origin of the six-layered isocortex from a primitive three-layered cortex. It is argued that the superficial isocortical layers can be considered to be an evolutionary acquisition of the mammalian brain, since no equivalent structures can be found in the reptilian brain. Furthermore, a characteristic of the isocortex is that it develops according to an inside-out neurogenetic gradient, in which late-produced cells migrate past layers of early-produced cells. It is proposed that the inside-out neurogenetic gradient was partly achieved by the activation of a signaling pathway associated with the Cdk5 kinase and its activator p35, while an extracellular protein called reelin (secreted in the marginal zone during development) may have prevented migrating cells from penetrating into the developing marginal zone (future layer I).
Asunto(s)
Evolución Biológica , Moléculas de Adhesión Celular Neuronal/fisiología , Corteza Cerebral/anatomía & histología , Proteínas de la Matriz Extracelular/fisiología , Proteínas del Tejido Nervioso/fisiología , Animales , Aves , Regulación del Desarrollo de la Expresión Génica , Mamíferos , Filogenia , Proteína Reelina , Reptiles , Serina Endopeptidasas , Olfato , Vías VisualesRESUMEN
Reelin is an extracellular matrix protein that is defective in reeler mutant mice and plays a key role in the organization of architectonic patterns, particularly in the cerebral cortex. In mammals, a "reelin signal" is activated when reelin, secreted by Cajal-Retzius neurons, binds to receptors of the lipoprotein receptor family on the surface of cortical plate cells, and triggers Dab1 phosphorylation. As reelin is a key component of cortical development in mammals, comparative embryological studies of reelin expression were carried out during cortical development in non-mammalian amniotes (turtles, squamates, birds and crocodiles) in order to assess the putative role of reelin during cortical evolution. The data show that reelin is present in the cortical marginal zone in all amniotes, and suggest that reelin has been implicated in the evolution of the radial organization of the cortical plate in the synapsid lineage leading from stem amniotes to mammals, as well as in the lineage leading to squamates, thus providing an example of homoplastic evolution (evolutionary convergence). The mechanisms by which reelin instructs radial cortical organization in these two lineages seem different: in the synapsid lineage, a drastic amplification of reelin production occurred in Cajal-Retzius cells, whereas in squamates, in addition to reelin-secreting cells in the marginal zone, a second layer of reelin-producing cells developed in the subcortex. Altogether, our results suggest that the reelin-signaling pathway has played a significant role in shaping the evolution of cortical development.
Asunto(s)
Evolución Biológica , Moléculas de Adhesión Celular Neuronal/fisiología , Corteza Cerebral/embriología , Proteínas de la Matriz Extracelular/fisiología , Transducción de Señal/fisiología , Animales , Corteza Cerebral/anatomía & histología , Corteza Cerebral/química , Proteínas Fúngicas/fisiología , Modelos Neurológicos , Proteínas del Tejido Nervioso , ARN Mensajero , Proteína Reelina , Serina EndopeptidasasRESUMEN
The roughest-irregular chiasm C ( rst-irreC) gene of Drosophila melanogaster encodes a transmembrane glycoprotein containing five immunoglobulin-like domains in its extracellular portion and an intracytoplasmic tail rich in serine and threonine as well some conserved motifs suggesting signal transduction activity. In the compound eye, loss-of-function rst-irreC mutants lack the characteristic wave of programmed cell death happening in early pupa and which is essential for the elimination of the surplus interommatidial cells. Here we report an investigation on the role played by the Rst-irreC molecule in triggering programmed cell death. "In vivo" transient expression assays showed that deletion of the last 80 amino acids of the carboxyl terminus produces a form of the protein that is highly toxic to larvae. This toxicity is suppressed if an additional 47 amino acid long, glutamine-rich region ("opa-like domain"), is also removed from the protein. The results suggest the possibility that the opa-like domain and the carboxyl terminus act in concert to modulate rst-irreC function in apoptosis, and we discuss this implication in the context of the general mechanisms causing glutamine-rich neurodegenerative diseases in humans.
Asunto(s)
Apoptosis/fisiología , Moléculas de Adhesión Celular Neuronal/fisiología , Proteínas de Drosophila/fisiología , Drosophila/fisiología , Proteínas del Ojo , Glutamina/química , Proteínas de Insectos/fisiología , Aminoácidos/química , Aminoácidos/metabolismo , Animales , Moléculas de Adhesión Celular Neuronal/química , Moléculas de Adhesión Celular Neuronal/genética , Muerte Celular , Drosophila/efectos de los fármacos , Drosophila/genética , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Femenino , Proteínas de Insectos/química , Proteínas de Insectos/genética , Larva/efectos de los fármacos , PlásmidosRESUMEN
We propose an hypothesis on the evolutionary origin of the unique inside-out developmental gradient of the isocortex, in which deep layers originate before superficial layers. This contrasts with the development of the reptilian cortex, which originates in an outside-in gradient. In mice, a mutated protein, reelin, produces the reeler phenotype, whose cortex has an outside-in neurogenetic gradient like in reptiles. Reelin is normally located in the marginal layer of the developing cerebral cortex, and its normal function has been proposed to be a stop signal that prevents radially migrating cells from moving into the marginal zone. Additionally, mutations on the kinase Cdk5, or in its neuronal-specific activator p35, produce a deficit similar to reeler in that the neurogenetic gradient is outside-in. However, contrary to reeler, in which no cell-sparse layer I is observed, in these mice, a well-defined layer I exists, which suggests that migrating cells respond normally to reelin. Apparently, Cdk5/p35 participate in permitting cortical cells to move across pre-existing (earlier produced) cortical layers, in order to be able to contact reelin once they reach the marginal zone. We suggest that the evolutionary advent of the mammalian cortical inside-out gradient became partly possible through the activation of the Cdk5/p35 pathway, which permitted migrating cells to move across layers of older cells. At about the same time, reelin became an important element in cortical development as it prevented neuronal migration into the marginal zone (cortical layer I) and facilitated the migration of neurons past postmigratory elements.
Asunto(s)
Evolución Biológica , Corteza Cerebral/embriología , Modelos Neurológicos , Animales , Cadherinas/fisiología , Moléculas de Adhesión Celular Neuronal/fisiología , Quinasa 5 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/fisiología , Embrión de Mamíferos/fisiología , Embrión no Mamífero , Proteínas de la Matriz Extracelular/fisiología , Proteínas del Tejido Nervioso/fisiología , Proteína Reelina , Serina EndopeptidasasRESUMEN
The cell adhesion molecule Rst-irreC is a transmembrane glycoprotein of the immunoglobulin superfamily involved in several important developmental processes in Drosophila, including axonal pathfinding in the optic lobe and programmed cell death and pigment cell differentiation in the pupal retina. As an initial step towards the "in vivo" functional analysis of this protein we have generated transgenic fly stocks carrying a truncated cDNA construct encoding only the extracellular domain of Rst-IrreC under the transcriptional control of the heat shock inducible promoter hsp70. We show that heat-shocking embryos bearing the transgene during the first 8hs of development lead to a 3-4 fold reduction in their viability compared to wild type controls. The embryonic lethality can already be produced by applying the heat pulse in the first 3hs of embryonic development, does not seem to be suppressed in the absence of wildtype product and is progressively reduced as the heat treatment is applied later in embryogenesis. These results are compatible with the hypothesis of the lethal phenotype being primarily due to heterophilic interactions between Rst-IrreC extracellular domain and an yet unknown ligand.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Proteínas de Drosophila , Drosophila melanogaster/genética , Proteínas del Ojo , Genes de Insecto/genética , Genes Letales/fisiología , Proteínas de Insectos/genética , Transgenes/fisiología , Animales , Moléculas de Adhesión Celular Neuronal/fisiología , Embrión no Mamífero/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica , Calor , Proteínas de Insectos/fisiología , Masculino , Fenotipo , ChoqueRESUMEN
The cell adhesion molecule Rst-irreC is a transmembrane glycoprotein of the immunoglobulin superfamily involved in several important developmental processes in Drosophila, including axonal pathfinding in the optic lobe and programmed cell death and pigment cell differentiation in the pupal retina. As an initial step towards the "in vivo" functional analysis of this protein we have generated transgenic fly stocks carrying a truncated cDNA construct encoding only the extracellular domain of Rst-IrreC under the transcriptional control of the heat shock inducible promoter hsp70. We show that heat-shocking embryos bearing the transgene during the first 8hs of development lead to a 3-4 fold reduction in their viability compared to wild type controls. The embryonic lethality can already be produced by applying the heat pulse in the first 3hs of embryonic development, does not seem to be suppressed in the absence of wildtype product and is progressively reduced as the heat treatment is applied later in embryogenesis. These results are compatible with the hypothesis of the lethal phenotype being primarily due to heterophilic interactions between Rst-IrreC extracellular domain and an yet unknown ligand.
Asunto(s)
Animales , Masculino , Femenino , Moléculas de Adhesión Celular Neuronal/genética , Drosophila melanogaster/genética , Embrión no Mamífero/fisiología , Expresión Génica , Genes Letales/fisiología , Transgenes/fisiología , Moléculas de Adhesión Celular Neuronal/fisiología , Genes de Insecto/genética , Calor , Fenotipo , ChoqueRESUMEN
Many adhesion molecules of the immunoglobulin superfamily expressed in the nervous system are attached to the neuronal membrane by a glycan-phosphatidylinositol. Using neuronal glycoprotein F3 as a model we will discuss how this lipid modification might confer on molecules specific properties which may be particularly well suited to a role in modulating neuronal interactions. In particular, the following data dealing with the question of how the glycosylphosphatidylinositol (GPI) anchor influences the function, transport and localization of this molecule will be presented. 1) When anchored to the plasma membrane, F3 fulfills the operational criteria of an adhesion molecule while its soluble form is able to stimulate neurite outgrowth of sensory neurons in culture. 2) In the hypothalamo-hypophyseal system, immunoblot analysis indicates that there is more F3 in the neurohypophysis where secretory axons terminate than in the hypothalamic nuclei where the molecule is synthesized. In addition, GPI-linked forms predominate in the nuclei while there are mainly soluble forms in the neurohypophysis, suggesting that there is conversion of the GPI-bearing form to the soluble form during axonal transport. 3) In the cerebellum, F3 is polarized to the tips of the axons of granule cells, the major neuronal population in this system, as an indication that indeed GPI might be a signal for targeting molecules to axons. However, some neurons such as Golgi cells express F3 over all their surface.