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The role of the reelin pathway in cortical development
Abstracts / Comparative Biochemistry and Physiology, Part B 126 (2000) S1-S108
T H E C O M P A R A T I V E P H Y S I O L O G Y O F P U L M O N A R Y S U R F A C T A N T : T H E N E X T 20 YEARS Christopher B. Daniels Dept o f Environmental Biology, University o f Adelaide, SA 5005, AUSTRALIA Lung structure and function varies widely among the vertebrates. However, all vertebrates probably have a homologous surfactaat system, present in the stem ancestor of this phylum over 400 million years ago. Surfactant function also appears to have evolved from the more primitive role as an anti-adhesive, to the highly derived function of providing alveolar stability in the broncho-alveolar lung of mammals. Surfactant retains its malleable form within individuals by altering its composition in response to changes in temperature. Pattie completed the last major review of the field of the comparative physiology of pulmonary surfactant in 1976, so it is timely to close this symposium with some ideas for the future. Research into the comparative physiology of surfactant will include but not be limited to 1: Evolution of the system; particularly involving lipids and lipo-protein interactions, proteins, and the genes. We know little of invertebrate surfactants, or the system in birds. Furthermore the potential origin of the pulmonary system from gut and its roles in other tissues, will be explored. 2: The evolution of surfactant function: Functions including the interaction with antioxidant systems, protection against edema, to aid the muco-cillary escalator, interaction with elements of lung structure and to aid in immunity are all central to our understanding of the surfactant system in preventing disease. Unusual animal models will also provide "lateral" views into surfactant function. 3: The influence of temperature on the surface activity, lipids and lipo-proteins. 4: Control of the surfaetant system, especially stimulation of release, temperature induced regulation and cell stretch. 5: Development in utero and in ovo, the environmental stresses such as hypoxla and the control of development remain to be clarified. In my view the surfactant system is a nearly packaged system, located in a single cell and highly conserved, yet spectacularly complex. The surfactunt system is one of the best systems I know to examine evolutionary processes in physiology as well as gain important insights into gas transfer by complex organisms.
T H E ROLE OF THE REELIN PATHWAY IN CORTICAL D E V E L O P M E N T G. D'Arcangelo*, R. Homayouni, L. Keshvara, D. S. Rice, M. Sheldon and T. Curran. Dept Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, *Dept Pediatrics, Baylor College o f Medicin and The Cain Foundation Laboratories, Houston TX. A signaling pathway involving the extracellular protein Reelin and the intracellular adaptor protein Disabled-1 (Dabl) controls laminar formation during mammalian brain development. Mutant mice in which either the reelin or the dabl gene is disrupted are ataxie and display widespread neuronal ectopia in cortical structures such as the neocortex, the cerebellum and the hippocampus. Previous studies demonstrated that Reelin is a molecule that is secreted by cells in superficial layers of cortical structures, and that it signals the end of radial migration to Dabl-expressing neuroblasts. When neurons encounter Reelin, Dabl becomes phosphorylated on tyrosine residues and its turnover is increased. These events are associated with changes in cellular morphology and the formation of cortical layers. However, the cellular receptors that convey the Reelin signal to Dabl in migrating neurons were not known. Double knock out mice lacking two members of the low density lipoprotein receptor (LDLR) family, the very low density lipoprotein receptor CCLDLR) and the apolipoprotein E receptor 2 (ApoER2), exhibit a neurological phenotype identical to that of mice lacking reelin or dab1. We showed that transfected cells expressing either VLDLR or ApoER2 bind Reelin very avidly. VLDLR binds Reelin rapidly and with high affinity in the presence of calcium. Furthermore, the CR-50 monoclonal antibody, which inhibits Reelin function, blocks the association of Reelin with VLDL1L However, the CR-50 epitope region of Reelin is not sufficient for binding to lipoprotein receptors. After binding VLDLR on the cell surface, Reelin is internalized into endocytic vesicles. Apolipoprotein E, a ligand for lipoprotein receptors, reduced the binding of Reelin to VLDLR and ApoER2 in transfected cells as well as the level of Dabl tyrosine phosphorylation in dissociated neurons. These data indicate that VLDLR and ApoER2 are Reelin receptors that function during the formation of cortical layers.
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T H E C O M P A R A T I V E P H Y S I O L O G Y O F P U L M O N A R Y S U R F A C T A N T : T H E N E X T 20 YEARS Christopher B. Daniels Dept o f Environmental Biology, University o f Adelaide, SA 5005, AUSTRALIA Lung structure and function varies widely among the vertebrates. However, all vertebrates probably have a homologous surfactaat system, present in the stem ancestor of this phylum over 400 million years ago. Surfactant function also appears to have evolved from the more primitive role as an anti-adhesive, to the highly derived function of providing alveolar stability in the broncho-alveolar lung of mammals. Surfactant retains its malleable form within individuals by altering its composition in response to changes in temperature. Pattie completed the last major review of the field of the comparative physiology of pulmonary surfactant in 1976, so it is timely to close this symposium with some ideas for the future. Research into the comparative physiology of surfactant will include but not be limited to 1: Evolution of the system; particularly involving lipids and lipo-protein interactions, proteins, and the genes. We know little of invertebrate surfactants, or the system in birds. Furthermore the potential origin of the pulmonary system from gut and its roles in other tissues, will be explored. 2: The evolution of surfactant function: Functions including the interaction with antioxidant systems, protection against edema, to aid the muco-cillary escalator, interaction with elements of lung structure and to aid in immunity are all central to our understanding of the surfactant system in preventing disease. Unusual animal models will also provide "lateral" views into surfactant function. 3: The influence of temperature on the surface activity, lipids and lipo-proteins. 4: Control of the surfaetant system, especially stimulation of release, temperature induced regulation and cell stretch. 5: Development in utero and in ovo, the environmental stresses such as hypoxla and the control of development remain to be clarified. In my view the surfactant system is a nearly packaged system, located in a single cell and highly conserved, yet spectacularly complex. The surfactunt system is one of the best systems I know to examine evolutionary processes in physiology as well as gain important insights into gas transfer by complex organisms.
T H E ROLE OF THE REELIN PATHWAY IN CORTICAL D E V E L O P M E N T G. D'Arcangelo*, R. Homayouni, L. Keshvara, D. S. Rice, M. Sheldon and T. Curran. Dept Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, *Dept Pediatrics, Baylor College o f Medicin and The Cain Foundation Laboratories, Houston TX. A signaling pathway involving the extracellular protein Reelin and the intracellular adaptor protein Disabled-1 (Dabl) controls laminar formation during mammalian brain development. Mutant mice in which either the reelin or the dabl gene is disrupted are ataxie and display widespread neuronal ectopia in cortical structures such as the neocortex, the cerebellum and the hippocampus. Previous studies demonstrated that Reelin is a molecule that is secreted by cells in superficial layers of cortical structures, and that it signals the end of radial migration to Dabl-expressing neuroblasts. When neurons encounter Reelin, Dabl becomes phosphorylated on tyrosine residues and its turnover is increased. These events are associated with changes in cellular morphology and the formation of cortical layers. However, the cellular receptors that convey the Reelin signal to Dabl in migrating neurons were not known. Double knock out mice lacking two members of the low density lipoprotein receptor (LDLR) family, the very low density lipoprotein receptor CCLDLR) and the apolipoprotein E receptor 2 (ApoER2), exhibit a neurological phenotype identical to that of mice lacking reelin or dab1. We showed that transfected cells expressing either VLDLR or ApoER2 bind Reelin very avidly. VLDLR binds Reelin rapidly and with high affinity in the presence of calcium. Furthermore, the CR-50 monoclonal antibody, which inhibits Reelin function, blocks the association of Reelin with VLDL1L However, the CR-50 epitope region of Reelin is not sufficient for binding to lipoprotein receptors. After binding VLDLR on the cell surface, Reelin is internalized into endocytic vesicles. Apolipoprotein E, a ligand for lipoprotein receptors, reduced the binding of Reelin to VLDLR and ApoER2 in transfected cells as well as the level of Dabl tyrosine phosphorylation in dissociated neurons. These data indicate that VLDLR and ApoER2 are Reelin receptors that function during the formation of cortical layers.
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