BMC Neuroscience | |
Reelin expression in brain endothelial cells: an electron microscopy study | |
Hector J Caruncho2  Erin Y Fenton2  Emma Perez-Costas1  | |
[1] Department of Psychology, University of Alabama at Birmingham, College of Arts and Sciences, Campbell Hall 415, 1720 2nd Avenue South, Birmingham 35294, Alabama, USA;Division of Pharmacy, College of Pharmacy and Nutrition, University of Saskatchewan, 1B23 Health Sciences Building, 107 Wiggins Road, Saskatoon S7N 5E5, SK, Canada | |
关键词: Brain capillaries; Transcytosis; Blood-brain-barrier; | |
Others : 1170552 DOI : 10.1186/s12868-015-0156-4 |
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received in 2014-11-04, accepted in 2015-03-11, 发布年份 2015 | |
【 摘 要 】
Background
Reelin expression and function have been extensively studied in the brain, although its expression has been also reported in other tissues including blood. This raises the possibility that reelin might be able to cross the blood-brain barrier, which could be functionally relevant. Up-to-date no studies have been conducted to assess if reelin is present in the blood-brain barrier, which is mainly constituted by tightly packed endothelial cells. In this report we assessed the expression of reelin in brain capillaries using immunocytochemistry and electron microscopy.
Results
At the light microscope, reelin immunolabeling appeared in specific endothelial cells in brain areas that presented abundant diffuse labeling for this protein (e.g., layer I of the cortex, or the stratum lacunosum moleculare of the hippocampus), while it was mostly absent from capillaries in other brain areas (e.g., deeper cortical layers, or the CA1 layer of the hippocampus). As expected, at the electron microscope reelin labeling was observed in neurons of the cortex, where most of the labeling was associated with the rough endoplasmic reticulum. Importantly, reelin was also observed in some endothelial cells located in small capillaries, which confirmed the findings obtained at the light microscope. In these cells, reelin labeling was located primarily in caveolae (i.e., vesicles of transcytosis), and associated with the plasma membrane of the luminal side of endothelial cells. In addition, some scarce labeling was observed in the nuclear membrane.
Conclusions
The presence of reelin immunolabeling in brain endothelial cells, and particularly in caveolar vesicles within these cells, suggests that reelin and/or reelin peptides may be able to cross the blood-brain barrier, which could have important physiological, pathological, and therapeutic implications.
【 授权许可】
2015 Perez-Costas et al.; licensee BioMed Central.
【 预 览 】
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20150417021458605.pdf | 2541KB | download | |
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Figure 1. | 151KB | Image | download |
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【 参考文献 】
- [1]D’Arcangelo G, Miao GG, Chen S-C, Soares HD, Morgan JI, Curran T: A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 1995, 374:719-723.
- [2]Tissir F, Goffinet AM: Reelin and brain development. Nat Rev Neurosci 2003, 4:496-595.
- [3]Forster E, Bock HH, Herz J, Chai X, Frotscher M, Zhao S: Emerging topics in reelin function. Eur J Neurosci 2010, 31:1511-1518.
- [4]Lakatosova S, Ostatnikova D: Reelin and its complex involvement in brain development and function. Int J Biochem & Cell Biol 2012, 44:1501-1504.
- [5]Stranahan AM, Erion JR, Wosiski-Kuhn M: Reelin signaling in development, maintenance, and plasticity of neuronal networks. Ageing Res Rev 2013, 12:815-822.
- [6]Alcantara S, Ruiz M, D’Arcangelo G, Ezan F, de Lecea L, Curran T, et al.: Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse. J Neurosci 1998, 18:7779-7799.
- [7]Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A, et al.: Reelin is preferentially expressed in neurons synthesizing g-aminobutyric acid in cortex and hippocampus of adult rats. Proc Natl Acad Sci USA 1998, 95:3221-3226.
- [8]Pesold C, Liu WS, Guidoti A, Costa E, Caruncho HJ: Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression. Proc Natl Acad Sci USA 1999, 96:3217-3222.
- [9]Ramos-Moreno T, Galazo MJ, Porrero C, Martinez-Cerdeño V, Clasca F: Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted reelin in the adult rat brain. Eur J Neurosci 2006, 23:401-422.
- [10]Pohlkamp T, David C, Cauli B, Gallopin T, Bouche E, Karagiannis A, et al.: Characterization and distribution of reelin-positive interneurons in the rat barrel cortex. Cereb Cortex 2014, 24:3046-3058.
- [11]Hellwig S, Hack I, Kowalski J, Brunne B, Jarowyj J, Unger A, et al.: Role for reelin in neurotransmitter release. J Neurosci 2011, 31:2352-2360.
- [12]Bal M, Leitz J, Reese AL, Ramirez DMO, Durakoglugil M, Herz J, et al.: Reelin mobilizes a VAMP-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission. Neuron 2013, 80:934-946.
- [13]Rodriguez MA, Pesold C, Liu WS, Kriho V, Guidotti A, Pappas GD, et al.: Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult non-human primate cortex. Proc Natl Acad Sci USA 2000, 97:3550-3555.
- [14]Niu S, Yabut O, D’Arcangelo G: The reelin signaling pathway promotes dendritic spine development in hippocampal neurons. J Neurosci 2008, 28:10339-10448.
- [15]Charneau P, Inta D, Vitalis T, Monyer H, Wadman WJ, van Hooft JA: The N-terminal region of reelin regulates postnatal dendritic maturation of cortical pyramidal neurons. Proc Natl Acad Sci USA 2009, 106:7227-7232.
- [16]Kupferman JV, Basu J, Russo MJ, Guevarra J, Cheung SK, Siegelbaum SA: Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment. Cell 2014, 158:1335-1347.
- [17]Gonzalez-Campo C, Sinagra M, Verrier D, Manzoni OJ, Chavis P: Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis. PLoS One 2009, 4:e5505.
- [18]Gong C, Wang TW, Huang HS, Parent JM: Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci 2007, 27:1803-1811.
- [19]Zhao S, Chai X, Frotscher M: Balance between neurogenesis and gliogenesis in the adult hippocampus: role for reelin. Dev Neurosci 2007, 29:84-90.
- [20]Lussier AL, Caruncho HJ, Kalynchuk LE: Repeated exposure to corticosterone, but not restraint, decreases the humber of reelin-positive cells in the adult rat hippocampus. Neurosci Lett 2009, 460:170-174.
- [21]Lussier AL, Romay-Tallon R, Kalynchuk LE, Caruncho HJ: Reelin as a putative vulnerability factor for depression: Examining the depressogenic effects of repeated corticosterone in heterozygous reeler mice. Neuropharmacology 2011, 60:1064-1074.
- [22]Lussier AL, Lebedeva K, Fenton EY, Guskjolen A, Caruncho HJ, Kalynchuk LE: The progressive development of depression-like behavior in corticosterone-treated rats is paralleled by slowed granule cell maturation and decreased reelin expression in the adult dentate gyrus. Neuropharmacology 2013, 71:174-183.
- [23]Fournier NM, Andersen DR, Botterill JJ, Sterner EY, Lussier AL, Caruncho HJ, et al.: The effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus. Hippocampus 2010, 20:659-671.
- [24]Pujadas L, Gruart A, Bosch C, Delgado L, Teixeira CM, Rossi D, et al.: Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J Neurosci 2010, 30:4636-4649.
- [25]Teixeira CM, Kron MM, Masachs N, Zhang H, Lagace DC, Martinez A, et al.: Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus. J Neurosci 2012, 32:12051-12065.
- [26]Bottner M, Ghorbani P, Harde J, Barrenschee M, Hellwig I, Vogel I, et al.: Expression and regulation of reelin and its receptors in the enteric nervous system. Mol Cell Neurosci 2014, 61:23-33.
- [27]Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, et al.: Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adremal chromaffin cells. Proc Natl Acad Sci USA 2000, 97:1281-1286.
- [28]Tseng W-L, Huand C-L, Chong K-Y, Liao C-H, Stern A, Cheng J-C, et al.: Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen. Cell Mol Life Sci 2010, 67:641-653.
- [29]Samama B, Boehm N: Reelin immunoreactivity in lymphatics and liver during development and adult life. Anat Rec Part A 2005, 285A:595-599.
- [30]Lutter S, Xie S, Tatin F, Makinen T: Smooth muscle-endothelial cell communication activates reelin signaling and regulates lymphatic vessel formation. J Cell Biol 2014, 197:837-849.
- [31]Derer P, Derer M, Goffinet A: Axonal secretion of reelin by Cajal-Retzius cells: evidence form comparison of normal and RelnOrl mutant mice. J Comp Neurol 2001, 440:136-143.
- [32]Pappas GD, Kriho V, Pesold C: Reelin in the extracellular matrix and dendritic spines of the cortex and hippocampus: a comparison between wild type and heterozygous reeler mice by immunoelectron microscopy. J Neurocytol 2001, 30:413-425.
- [33]Pappas GD, Kriho V, Liu WS, Tremolizzo L, Lugli G, Larson J: Immunocytochemical localization of reelin in the olfactory bulb of the heterozygous reeler mouse: an animal model for schizophrenia. Neurol Res 2003, 25:819-830.
- [34]Martinez-Cerdeño V, Galazo MJ, Cavada C, Clasca F: Reelin immunoreactivity in the adult primate brain: Intracellular localization in projecting and local circuit neurons of the cerebral cortex, hippocampus and subcortical regions. Cereb Cortex 2002, 12:1298-1311.
- [35]Roberts RC, Xu L, Roche JK, Kirkpatrick B: Ultrastructural localization of reelin in the cortex in post-mortem human brain. J Comp Neurol 2006, 482:294-308.
- [36]Inoue K: A new approach to the quantitative analysis of the vascular architecture and its application to the cerebral cortex of the reeler mouse. Hokkaido Igaku Zasshi 1990, 65:493-509.
- [37]Riddell DR, Sun X-M, Stannard AK, Soutar AK, Owen JS: Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane. J Lipid Res 2001, 42:998-1002.
- [38]Cuitino L, Matute R, Retamal C, Bu G, Inestrosa NC, Marzolo MP: ApoER2 is endocytosed by a clathrin-mediated process involving the adaptor protein Dab2 independent of its rafts’ association. Traffic 2005, 6:820-838.
- [39]Mayer H, Duit S, Hauser C, Schneider WJ, Nimpf J: Reconstitution of the reelin signaling pathway in fibroblasts demonstrates that Dab1 phosphorylation is independent of receptor localization in lipid rafts. Mol Cell Biol 2006, 26:19-27.
- [40]Minami SS, Hoe H-S, Rebeck GW: Fyn kinase regulates the association between amyloid precursor protein and Dab1 by promoting their localization to detergent-resistant membranes. J Neurochem 2011, 118:879-890.
- [41]Strasser V, Fasching D, Hauser C, Mayer H, Bock HH, Hiesberger T, et al.: Receptor clustering is involved in reelin signaling. Mol Cell Biol 2004, 24:1378-1386.
- [42]Divekar SD, Burrell TC, Lee JE, Weeber EJ, Rebeck GW: Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2. J Biol Chem 2014, 289:15894-15903.
- [43]Duit S, Mayer H, Blake SM, Schneider WJ, Nimpf J: Differential functions of ApoER2 and very low density lipoprotein receptor in reelin signaling depend on differential sorting of the receptors. J Biol Chem 2010, 285:4896-4908.
- [44]Rivera-Baltanas T, Romay-Tallon R, Dopeso-Reyes IG, Caruncho HJ: Serotonin transporter clustering in blood lymphcoytes of reeler mice. Cardiovasc Psychiatry Neurol 2010, 2010:396282.
- [45]Dong E, Caruncho H, Liu WS, Smalheiser NR, Grayson DR, Costa E, et al.: A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes. Proc Natl Acad Sci USA 2003, 100:5479-5484.
- [46]Caruncho HJ, Dopeso-Reyes IG, Loza MI, Rodriguez MA: GABA, reelin, and the neurodevelopmental hypothesis of schizophrenia. Crit Rev Neurobiol 2004, 16:25-32.
- [47]Fatemi SH, Earle JA, McMenomy T: Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 2000, 5:654-663.
- [48]Fatemi SH, Kroll JL, Stary JM: Altered levels of reelin and its isoforms in schizophrenia and mood disorders. Neuroreport 2001, 12:3209-3215.
- [49]Rivera-Baltanas T, Olivares JM, Calado-Otero M, Kalynchuk LE, Martinez-Villamarin JR, Caruncho HJ: Serotonin transporter clustering in blood lymphocytes as a putative biomarker of therapeutic efficacy in major depressive disorder. J Affect Disord 2012, 137:46-55.
- [50]Rivera-Baltanas T, Olivares JM, Martinez-Villamarin JR, Fenton EY, Kalynchuk LE, Caruncho HJ: Serotonin 2A receptor clustering in peripheral lymphocytes is altered in major depression and may be a biomarker of therapeutic efficacy. J Affect Disord 2014, 163:47-55.
- [51]Teixeira CM, Martin ED, Sahun I, Masachs N, Pujadas L, Corvelo A, et al.: Overexpression of reelin prevents the manifestation of behavioral phenotypes related to schizophrenia and bipolar disorder. Neuropsychopharmacol 2011, 36:2395-2405.
- [52]Perez-Costas E, Gandy JC, Melendez-Ferro M, Roberts RC, Bijur GN. Light and electron microscopy study of glycogen synthase kinase-3β in the mouse brain. PLoS ONE. 2010; 5(1): e8911. doi:10.1371/journal.pone.0008911