FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W7267396> ?p ?o ?g. }

• W7267396 endingPage "674" @default.
• W7267396 startingPage "671" @default.
• W7267396 abstract "While some nutrients enter cells through transporters, others, including iron and cholesterol, are actively imported into cells by specialized receptors. These import receptors continuously recycle between the cell surface and intracellular vesicles. Cargo is carried from the cell surface via clathrin-coated pits to endosomes, acidified compartments where the cargo is released. The receptors then return to the cell surface for another cycle of import. One import receptor, the low density lipoprotein receptor (LDLR), has been intensively studied because its malfunction is a cause of atherosclerosis. The LDLR is essential to transport LDL (complexes of cholesterol, triglycerides, and specific apolipoproteins) out of the plasma, as first shown by the hallmark analysis of familial hypercholesterolemia by Brown and Goldstein. In subsequent years, other import receptors related to the LDLR have been discovered, and the LDLR superfamily now includes at least five mammalian and several invertebrate proteins. It has become clear that most of the new members of the family do not have a primary function in LDL import, and instead bind and import multiple ligands (see Figure 1). Indeed, the ability to transport LDL is a recent evolutionary adaptation of an ancient receptor family. Even so, there have been few reasons to suspect that these proteins regulate cellular events during development. Thus, it is remarkable to discover that the ablation of two LDLR family members (VLDLR and ApoER2) causes very specific alterations in the development of the nervous system (Trommsdorff et al., 1999 [this issue of Cell]). Moreover, the characteristic changes in the mutant brains indicate that neurons interpret or respond to positional information with the help of VLDLR and ApoER2, which may therefore be signaling receptors. These findings herald a new opportunity for interactions between researchers in atherosclerosis and neurobiology. Brain development is markedly altered in mice lacking both VLDLR and ApoER2 (19Trommsdorff M. Gotthardt M. Hiesberger T. Shelton J. Stockinger W. Nimpf J. Hammer R.E. Richardson J.A. Herz J. Cell. 1999; 97 (this issue,): 689-701Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar). The double mutants have obvious and highly characteristic defects in neuronal layering in cerebral cortex, hippocampus, and cerebellum. Detailed analysis shows that the VLDLR− apoER2− phenotype is virtually identical to that seen when either of two other genes, reln (reelin) or dab1 (mammalian disabled-1), is mutated. Extensive neuroanatomical and cell marking analysis of reln mutant mice, and more recent analysis of dab1 mutant mice, has shown that the defective layering is due to misplacement of committed neurons (5Goldowitz D. Cushing R.C. Laywell E. D’Arcangelo G. Sheldon M. Sweet H.O. Davisson M. Steindler D. Curran T. J. Neurosci. 1997; 17: 8767-8777PubMed Google Scholar, 6Gonzalez J.L. Russo C.J. Goldowitz D. Sweet H.O. Davisson M.T. Walsh C.A. J. Neurosci. 1997; 17: 9204-9211PubMed Google Scholar, 8Howell B.W. Hawkes R. Soriano P. Cooper J.A. Nature. 1997; 389: 733-737Crossref PubMed Scopus (619) Google Scholar, 11Lambert de Rouvroit C. Goffinet A.M. Adv. Anat. Embryol. Cell Biol. 1998; 150: 1-106Crossref PubMed Google Scholar). That is, each neuron adopts its correct fate but in the wrong place. This occurs most conspicuously in the cerebral cortex, hippocampus, and cerebellum. Each of these parts of the brain has a characteristic architecture of packed layers of cells with specific functional identities. In VLDLR− apoER2−, reln−, and dab1− brains, these layers are disorganized. For example, the Purkinje cells of the cerebellum normally migrate outward from an origin near the fourth ventricle, to form a thin layer beneath cerebellar granule cell precursors. In the mutants, the Purkinje cells initiate migration but remain clustered deeper in the cerebellar primordium (11Lambert de Rouvroit C. Goffinet A.M. Adv. Anat. Embryol. Cell Biol. 1998; 150: 1-106Crossref PubMed Google Scholar, 19Trommsdorff M. Gotthardt M. Hiesberger T. Shelton J. Stockinger W. Nimpf J. Hammer R.E. Richardson J.A. Herz J. Cell. 1999; 97 (this issue,): 689-701Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar). Since the proliferation of granule cells requires mitogens, such as Sonic hedgehog, made by the Purkinje cells, the number of granule cells is markedly reduced in the mutants, and the mutant cerebella are about five times smaller than usual. The development of the cortex is orchestrated differently (15Pearlman A.L. Faust P.L. Hatten M.E. Brunstrom J.E. Curr. Opin. Neurobiol. 1998; 8: 45-54Crossref PubMed Scopus (113) Google Scholar). Early neurons form two layers, an inner subplate and an outer layer of Cajal-Retzius (CR) neurons. Later neurons, which will form the cortical plate of the embryonic cortex, move through the subplate layer and come to rest below the CR cells. As each subsequent cortical plate neuron migrates, it bypasses its predecessors, coming to rest immediately below the CR neurons. In the mutants, the migrating cells neither penetrate between subplate neurons nor overtake their brethren (15Pearlman A.L. Faust P.L. Hatten M.E. Brunstrom J.E. Curr. Opin. Neurobiol. 1998; 8: 45-54Crossref PubMed Scopus (113) Google Scholar, 16Rice D.S. Sheldon M. D’Arcangelo G. Nakajima K. Goldowitz D. Curran T. Development. 1998; 125: 3719-3729Crossref PubMed Google Scholar). The CR, subplate, and early cortical plate neurons remain superficial to subsequent generations of cortical plate neurons, which pile-up underneath them as the brain expands. It is clear that neurons in the affected regions of the brain can and do migrate, but they seem to lack the ability to sense their position and respond appropriately. The characterization of the reln and dab1 genes has made it possible to interpret the complex neuroanatomical defects of the mutants in terms of a signaling pathway. The reln gene encodes a large glycoprotein (Reln) that is secreted by specialized neurons within restricted regions of the brain (3D’Arcangelo G. Miao G.G. Chen S.C. Soares H.D. Morgan J.I. Curran T. Nature. 1995; 374: 719-723Crossref PubMed Scopus (1487) Google Scholar, 13Ogawa M. Miyata T. Nakajima K. Yagyu K. Seike M. Ikenaka K. Yamamoto H. Mikoshiba K. Neuron. 1995; 14: 899-912Abstract Full Text PDF PubMed Scopus (776) Google Scholar). In the cerebellar primordium, Reln is made by the external layer of granule cells, and by the deep nuclei, below the Purkinje cells, but not by the Purkinje cells themselves. This suggests that Purkinje cell position is influenced by external signals, in the form of Reln. In the cortex, Reln is made by the CR neurons but not by the migratory cells (3D’Arcangelo G. Miao G.G. Chen S.C. Soares H.D. Morgan J.I. Curran T. Nature. 1995; 374: 719-723Crossref PubMed Scopus (1487) Google Scholar, 13Ogawa M. Miyata T. Nakajima K. Yagyu K. Seike M. Ikenaka K. Yamamoto H. Mikoshiba K. Neuron. 1995; 14: 899-912Abstract Full Text PDF PubMed Scopus (776) Google Scholar). Early in development, it induces a change that allows cortical neurons through the subplate. Later, as the CR neurons are displaced outward, the zone of Reln production marks the stopping point for each wave of migrating cortical neurons. Reln may instruct these neurons to stop migrating and to allow subsequent arrivals to pass by. Thus, in reln− animals, cortical plate neurons can migrate but cannot pass through the subplate or overtake other cortical plate neurons. There is also evidence that Reln influences the targeting of specific axons, suggesting that Reln may also mark the stopping points for axonal growth cones (4Del Río J.A. Heimrich B. Borrell V. Forster E. Drakew A. Alcántara S. Nakajima K. Miyata T. Ogawa M. Mikoshiba K. Derer P. Frotscher M. Soriano E. Nature. 1997; 385: 70-74Crossref PubMed Scopus (407) Google Scholar). The cellular responses induced by Reln, and how they contribute to the anatomical defects, are still mysterious. In principle, changes in motility, adhesion, or gene expression (e.g., of chemotaxis receptors) could be important. One clue is that neurons from reln− brains have increased homotypic adhesion in vitro (7Hoffarth R.M. Johnston J.G. Krushel L.A. Van der Kooy D. J. Neurosci. 1995; 15: 4838-4850Crossref PubMed Google Scholar, 13Ogawa M. Miyata T. Nakajima K. Yagyu K. Seike M. Ikenaka K. Yamamoto H. Mikoshiba K. Neuron. 1995; 14: 899-912Abstract Full Text PDF PubMed Scopus (776) Google Scholar). In vitro assays for Reln-regulated cell migration are currently unavailable but will be crucial to understanding the chain of events. The dab1 gene encodes a cytoplasmic, tyrosine-phosphorylated protein that is found in the neurons whose migrations are altered in each part of the brain, including Purkinje cells and cortical plate neurons (8Howell B.W. Hawkes R. Soriano P. Cooper J.A. Nature. 1997; 389: 733-737Crossref PubMed Scopus (619) Google Scholar, 16Rice D.S. Sheldon M. D’Arcangelo G. Nakajima K. Goldowitz D. Curran T. Development. 1998; 125: 3719-3729Crossref PubMed Google Scholar). Therefore, Dab1 seems likely to be part of the response to a signal from Reln. Indeed, Dab1 tyrosine phosphorylation is stimulated directly by Reln in neuronal cultures, and Dab1 tyrosine phosphorylation is reduced in the brains of embryos that lack Reln (9Howell B.W. Herrick T.M. Cooper J.A. Genes Dev. 1999; 13: 643-648Crossref PubMed Scopus (355) Google Scholar). Thus, Reln is likely to act, in whole or in part, by stimulating tyrosine phosphorylation of Dab1. Consistent with this implied order of events, Dab1 is not required for Reln expression, and Reln has no detectable Dab1-independent functions. In addition, Reln regulates Dab1 protein levels, such that Dab1 protein levels increase conspicuously in brains that lack Reln (16Rice D.S. Sheldon M. D’Arcangelo G. Nakajima K. Goldowitz D. Curran T. Development. 1998; 125: 3719-3729Crossref PubMed Google Scholar, 9Howell B.W. Herrick T.M. Cooper J.A. Genes Dev. 1999; 13: 643-648Crossref PubMed Scopus (355) Google Scholar). Although VLDLR− apoER2− mice phenocopy reln− and dab1− mutants, analysis of single mutants suggests that the VLDLR is more important in the cerebellum while ApoER2 is more important in the cortex (19Trommsdorff M. Gotthardt M. Hiesberger T. Shelton J. Stockinger W. Nimpf J. Hammer R.E. Richardson J.A. Herz J. Cell. 1999; 97 (this issue,): 689-701Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar). This is consistent with higher expression of VLDLR, relative to ApoER2, in the cerebellum than in the cortex. Therefore, VLDLR and ApoER2 may be functionally redundant in a mechanistic sense, with each receptor working identically and its relative importance determined solely by its abundance. However, the simple hypothesis of a common molecular mechanism of action raises the question of why closely related proteins that are also expressed in the developing cortex and cerebellum, such as LRP and the LDLR, do not compensate for lack of VLDLR and ApoER2 in the mutants. On the other hand, it is also possible that the VLDLR and ApoER2 have distinct molecular mechanisms of action in the cerebellum and cortex, respectively. For example, they may interact with cerebellum-specific and cortex-specific effectors, respectively. “Knocking-in” one receptor gene into the other’s genomic locus may be needed to resolve the question of redundant versus specialized functions. In support of the functional evidence that Reln, Dab1, VLDLR, and ApoER2 may be on the same pathway, biochemical studies suggest that there may be a direct physical link between VLDLR or ApoER2 and Dab1 (see Figure 1). The Dab1 protein contains a domain that binds specifically to an FXNPXY signal present in all LDLR family proteins (18Trommsdorff M. Borg J.-P. Margolis B. Herz J. J. Biol. Chem. 1998; 273: 33556-33560Crossref PubMed Scopus (489) Google Scholar). This sequence is also required for LDLR internalization, since it associates with clathrin and adaptor proteins (10Kibbey R.G. Rizo J. Gierasch L.M. Anderson R.G.W. J. Cell Biol. 1998; 142: 59-67Crossref PubMed Scopus (79) Google Scholar). Although a complex between VLDLR or ApoER2 and Dab1 has not yet been demonstrated in neurons, such complexes do form in vitro and in heterologous cells, and would provide a molecular mechanism for signals to be transmitted between the receptors and Dab1. It would also suggest that the receptors would work in the cells that express Dab1. Indeed, VLDLR and ApoER2 are expressed by the neurons that express Dab1, as well as other cells in the cerebellum and cortex, and are not expressed in the cells that make Reln (19Trommsdorff M. Gotthardt M. Hiesberger T. Shelton J. Stockinger W. Nimpf J. Hammer R.E. Richardson J.A. Herz J. Cell. 1999; 97 (this issue,): 689-701Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar). As in the dab1− brain, VLDLR− apoER2− neurons localize as though they have not sensed the Reln signal. In addition, Dab1 protein levels are increased, as in a reln− mutant. Coupled with the direct binding of Dab1 to the receptors, these results suggest that VLDLR and ApoER2 are part of the Reln response pathway, although a parallel pathway cannot be rigorously excluded at this time. Assuming a single signaling cascade raises the question: Do the receptors regulate Dab1, or conversely, does Dab1 regulate the receptors? An intriguing possibility is that VLDLR and ApoER2 may be cell surface receptors or coreceptors for Reln (Figure 2, left). If Reln does bind to the extracellular domain of either VLDLR or ApoER2, it may allow the receptor to bring its associated Dab1 close to a tyrosine kinase for phosphorylation. Such a kinase may be contained in the cellular compartment through which the receptors cycle, such as coated pits, or may be supplied by a Reln coreceptor that has associated tyrosine kinase activity. It remains to be seen whether Reln actually binds to VLDLR and ApoER2, and whether the receptors are needed for Reln to induce Dab1 tyrosine phosphorylation in vivo and in cultured neurons. VLDLR and ApoER2 also have the potential to be effectors for the response (Figure 2, right). For example, they may regulate migration by controlling exocytosis of new membrane at the leading edge of the cell. Dab1 could regulate membrane trafficking by binding to the internalization signals of VLDLR and ApoER2 and interacting with the vesicle transport machinery. In addition, VLDLR has been shown to be a receptor for proteins that regulate cell motility in other systems. The motility of cultured epithelial cells is increased when the urokinase-type plasminogen activator (uPA) binds to the cell surface uPA receptor (uPAR) (20Webb D.J. Nguyen D.H.D. Sankovic M. Gonias S.L. J. Biol. Chem. 1999; 274: 7412-7420Crossref PubMed Scopus (104) Google Scholar). The uPAR lacks internalization signals, but the VLDLR acts as a coreceptor for internalization. VLDLR-mediated clearance of uPA and uPAR from the surface inhibits motility. If these cell culture experiments are relevant to neuronal migrations in vivo, these observations suggest that VLDLR and ApoER2 could play an effector role in a Reln–Dab1 signaling pathway by altering cell surface levels of proteases required for motility. Whether the receptors are upstream, downstream, or parallel to the Reln–Dab1 pathway, it is fairly certain that lipoproteins will not play an essential regulatory role in the phenotype. The only lipoproteins that bind to both VLDLR and ApoER2 have apolipoprotein E (ApoE) as their protein component. An apoE− knockout mouse has been made, and does not show any obvious abnormalities in brain development, although neurodegenerative symptoms are detected in later life (12Masliah E. Mallory M. Ge N. Alford M. Veinbergs I. Roses A.D. Exp. Neurol. 1995; 136: 107-122Crossref PubMed Scopus (358) Google Scholar). This suggests that ApoE lipoproteins will not play an instructive role in neuronal migrations. On the other hand, lipoproteins may regulate the levels of VLDLR and ApoER2 available for interaction with other ligands, and thus modify the response to Reln. As a corollary, Dab1 and similar proteins that bind the internalization signal of LDLR relatives could regulate receptor trafficking, and thus modify lipoprotein internalization kinetics. These possibilities remain to be explored. Mutations in some other genes cause phenotypes that are reminiscent of some aspects of the reln−, dab1− and VLDLR− apoER2− phenotype, suggesting they may be involved in the same signaling events. These genes encode a serine/threonine kinase, Cdk5, its stimulatory subunit, p35, and the integrin α3 (14Ohshima T. Ward J.M. Huh C.G. Longenecker G. Veeranna Pant H.C. Brady R.O. Martin L.J. Kulkarni A.B. Proc. Natl. Acad. Sci. USA. 1996; 93: 11173-11178Crossref PubMed Scopus (808) Google Scholar, 2Chae T. Kwon Y. Bronson R. Dikkes P. Li E. Tsai L. Neuron. 1997; 18: 29-42Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 1Anton E.S. Kreidberg J.A. Rakic P. Neuron. 1999; 22: 277-289Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). This suggests that serine/threonine phosphorylation and integrin function could be regulated by Dab1. However, these mutations do not give perfect phenocopies, suggesting that they may act on parallel pathways or on branches in the Reln–Dab1 pathway that are important in some cell types but not others. The existence of parallel or branched pathways may become apparent if compound homozygotes show synthetic phenotypes, but these crosses have not yet been reported. In addition, a number of human genetic disorders cause defects in neuronal migration, but none of the mapped genes has been associated with the Reln signaling pathway. Defects in the Reln pathway may have more serious consequences in human development and lead to embryonic death. In addition to a role in development, there is reason to believe that pathways regulated by VLDLR and ApoER2 may also be involved in neurodegenerative diseases. Individuals with specific alleles of apoE, app, ps1, or ps2 are predisposed to Alzheimer’s disease (17Tanzi R.E. Kovacs D.M. Kim T.W. Moir R.D. Guenette S.Y. Wasco W. Neurobiol. Dis. 1996; 3: 159-168Crossref PubMed Scopus (238) Google Scholar). The apoE gene encodes ApoE, which can bind to VLDLR or ApoER2. The app gene encodes the amyloid precursor protein (APP), a transmembrane protein that contains a YXNPXY internalization signal that binds Dab1. The ps1 and ps2 genes encode presenilins; apparent proteases or protease regulators involved in cleaving APP. The roles for Reln, Dab1, and the ApoE receptors in adult animals is presently unknown but now seems ripe for exploring." @default.
• W7267396 created "2016-06-24" @default.
• W7267396 creator A5033347099 @default.
• W7267396 creator A5072832150 @default.
• W7267396 date "1999-06-01" @default.
• W7267396 modified "2023-10-13" @default.
• W7267396 title "Lipoprotein Receptors" @default.
• W7267396 cites W1530869325 @default.
• W7267396 cites W1667992367 @default.
• W7267396 cites W1979890518 @default.
• W7267396 cites W1983795337 @default.
• W7267396 cites W2002437987 @default.
• W7267396 cites W2021958350 @default.
• W7267396 cites W2035176443 @default.
• W7267396 cites W2036838270 @default.
• W7267396 cites W2038901745 @default.
• W7267396 cites W2070651871 @default.
• W7267396 cites W2072701439 @default.
• W7267396 cites W2079396188 @default.
• W7267396 cites W2080306322 @default.
• W7267396 cites W2105660819 @default.
• W7267396 cites W2119766505 @default.
• W7267396 cites W2145697397 @default.
• W7267396 cites W2149131804 @default.
• W7267396 cites W2161002325 @default.
• W7267396 cites W2162321314 @default.
• W7267396 cites W32449160 @default.
• W7267396 doi "https://doi.org/10.1016/s0092-8674(00)80778-3" @default.
• W7267396 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/10380917" @default.
• W7267396 hasPublicationYear "1999" @default.
• W7267396 type Work @default.
• W7267396 sameAs 7267396 @default.
• W7267396 citedByCount "82" @default.
• W7267396 countsByYear W72673962013 @default.
• W7267396 countsByYear W72673962014 @default.
• W7267396 countsByYear W72673962016 @default.
• W7267396 countsByYear W72673962019 @default.
• W7267396 countsByYear W72673962020 @default.
• W7267396 countsByYear W72673962021 @default.
• W7267396 countsByYear W72673962022 @default.
• W7267396 crossrefType "journal-article" @default.
• W7267396 hasAuthorship W7267396A5033347099 @default.
• W7267396 hasAuthorship W7267396A5072832150 @default.
• W7267396 hasBestOaLocation W72673961 @default.
• W7267396 hasConcept C134018914 @default.
• W7267396 hasConcept C170493617 @default.
• W7267396 hasConcept C2776104379 @default.
• W7267396 hasConcept C2778163477 @default.
• W7267396 hasConcept C2780072125 @default.
• W7267396 hasConcept C43554185 @default.
• W7267396 hasConcept C54355233 @default.
• W7267396 hasConcept C70721500 @default.
• W7267396 hasConcept C86803240 @default.
• W7267396 hasConcept C95444343 @default.
• W7267396 hasConceptScore W7267396C134018914 @default.
• W7267396 hasConceptScore W7267396C170493617 @default.
• W7267396 hasConceptScore W7267396C2776104379 @default.
• W7267396 hasConceptScore W7267396C2778163477 @default.
• W7267396 hasConceptScore W7267396C2780072125 @default.
• W7267396 hasConceptScore W7267396C43554185 @default.
• W7267396 hasConceptScore W7267396C54355233 @default.
• W7267396 hasConceptScore W7267396C70721500 @default.
• W7267396 hasConceptScore W7267396C86803240 @default.
• W7267396 hasConceptScore W7267396C95444343 @default.
• W7267396 hasIssue "6" @default.
• W7267396 hasLocation W72673961 @default.
• W7267396 hasLocation W72673962 @default.
• W7267396 hasOpenAccess W7267396 @default.
• W7267396 hasPrimaryLocation W72673961 @default.
• W7267396 hasRelatedWork W1965746743 @default.
• W7267396 hasRelatedWork W1978747192 @default.
• W7267396 hasRelatedWork W1987726377 @default.
• W7267396 hasRelatedWork W2015843413 @default.
• W7267396 hasRelatedWork W2035598300 @default.
• W7267396 hasRelatedWork W2073466768 @default.
• W7267396 hasRelatedWork W2184636034 @default.
• W7267396 hasRelatedWork W2228325854 @default.
• W7267396 hasRelatedWork W42353675 @default.
• W7267396 hasRelatedWork W626425574 @default.
• W7267396 hasVolume "97" @default.
• W7267396 isParatext "false" @default.
• W7267396 isRetracted "false" @default.
• W7267396 magId "7267396" @default.
• W7267396 workType "article" @default.