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Mariko Nishibe, Yu Katsuyama, Toshihide Yamashita
The motor deficit of the reeler mutants has largely been considered cerebellum related, and the developmental consequences of the cortex on reeler motor behavior have not been examined. We herein showed that there is a behavioral consequence to reeler mutation in models examined at cortex-dependent bimanual tasks that require forepaw dexterity. Using intracortical microstimulation, we found the forelimb representation in the motor cortex was significantly reduced in the reeler. The reeler cortex required a significantly higher current to evoke skeletal muscle movements, suggesting the cortical trans-synaptic propagation is disrupted...
March 13, 2018: Brain Structure & Function
Juan R Martinez-Galan, Ana Verdejo, Elena Caminos
Disturbances in calcium homeostasis due to canonical transient receptor potential (TRPC) and/or store-operated calcium (SOC) channels can play a key role in a large number of brain disorders. TRPC channels are plasma membrane cation channels included in the transient receptor potential (TRP) superfamily. The most widely distributed member of the TRPC subfamily in the brain is TRPC1, which is frequently linked to group I metabotropic glutamate receptors (mGluRs) and to the components of SOC channels. Proposing TRPC/SOC channels as a therapeutic target in neurological diseases previously requires a detailed knowledge of the distribution of such molecules in the brain...
2018: Frontiers in Neuroanatomy
Kyle J Brymer, Erin Y Fenton, Lisa E Kalynchuk, Hector J Caruncho
Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT) injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-α inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes...
2018: Frontiers in Pharmacology
Tian-Tian Liu, Yi Li, Yi Shu, Bo Xiao, Li Feng
Ephrin‑B3 is important in the regulation of cell proliferation, differentiation and migration via cell‑cell contact, and can activate the reelin pathway during brain development. However, the effect of ephrin‑B3 on hippocampal neurogenesis and the reelin pathway in epilepsy remains to be fully elucidated. In the present study, the expression of ephrin‑B3 in pilocarpine‑induced status epilepticus (SE) rats was investigated. SYBR Green‑based reverse transcription‑quantitative polymerase chain reaction analysis, immunohistochemical labeling and western blot analysis were used to detect the gene and protein expression levels of ephrin‑B3 and reelin pathway proteins...
March 7, 2018: International Journal of Molecular Medicine
P A Zykin, I A Moiseenko, L A Tkachenko, R A Nasyrov, E A Tsvetkov, E I Krasnoshchekova
We studied peculiarities of the structure of human entorhinal cortex at weeks 20-26 of gestation (10 hemispheres). The samples were Nissl-stained and immunohistochemically treated with antibodies to parvalbumin, calretinin, calbindin, and cytoskeleton proteins (MAP2 and N200). 3D-reconstruction of the entorhinal cortex from serial sections was performed, caudomedial and rostrolateral areas were isolated. Parvalbumin+ cells in layer I, discrete distribution of layer II cells with colocalization of MAP2 and calretinin at the border with layer I, and two sublayers Va and Vb with MAP2+ neurons were typical for the caudomedial area...
March 4, 2018: Bulletin of Experimental Biology and Medicine
María D Vázquez-Carretero, Pablo García-Miranda, María S Balda, Karl Matter, María J Peral, Anunciación A Ilundain
Disabled-1 (Dab1) is an essential intracellular adaptor protein in the reelin pathway. Our previous studies in mice intestine showed that Dab1 transmits the reelin signal to cytosolic signalling pathways. Here, we determine the Dab1 isoform expressed in rodent small and large intestine, its subcellular location and co-localization with clathrin, caveolin-1 and N-Wasp. PCR and sequencing analysis reveal that rodent small and large intestine express a Dab1 isoform that misses three (Y198 , Y200 and Y220 ) of the five tyrosine phosphorylation sites present in brain Dab1 isoform (canonical) and contains nuclear localization and export signals...
February 19, 2018: Biochimica et Biophysica Acta
Trinidad Mata-Balaguer, Inmaculada Cuchillo-Ibañez, Miguel Calero, Isidro Ferrer, Javier Sáez-Valero
Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The β-amyloid protein (Aβ) impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Aβ42 on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH-SY5Y cells because ApoER2 C-terminal fragments (CTFs), generated after reelin binding, regulate reelin expression...
February 9, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Vincenzo Di Donato, Flavia De Santis, Shahad Albadri, Thomas Oliver Auer, Karine Duroure, Marine Charpentier, Jean-Paul Concordet, Christoph Gebhardt, Filippo Del Bene
A conserved organizational and functional principle of neural networks is the segregation of axon-dendritic synaptic connections into laminae. Here we report that targeting of synaptic laminae by retinal ganglion cell (RGC) arbors in the vertebrate visual system is regulated by a signaling system relying on target-derived Reelin and VLDLR/Dab1a on the projecting neurons. Furthermore, we find that Reelin is distributed as a gradient on the target tissue and stabilized by heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM)...
February 5, 2018: Neuron
Min Xu, Xiaoning Han, Rui Liu, Yanjun Li, Cui Qi, Zhongzhou Yang, Chunjie Zhao, Jun Gao
3-Phosphoinositide-dependent protein kinase-1 (PDK1) is crucial for the development of the dentate gyrus (DG), the first gateway receiving afferent inputs from the entorhinal cortex. However, the role of PDK1 in DG development is unclear. In the present study, by crossing Pdk1fl/fl mice with the Emx1-cre line, we identified that the ablation of PDK1 disrupted the development of DG via decreasing the proliferation, and increasing the differentiation of dentate neural progenitor cells, downregulating AKT activity and upregulating GSK3β signaling...
February 6, 2018: Cerebral Cortex
Corinne L Fairchild, Keiko Hino, Jisoo S Han, Adam M Miltner, Gabriel Peinado Allina, Caileigh E Brown, Marie E Burns, Anna La Torre, Sergi Simo
The laminated structure of the retina is fundamental for the organization of the synaptic circuitry that translates light input into patterns of action potentials. However, the molecular mechanisms underlying cell migration and layering of the retina are poorly understood. Here, we show that RBX2, a core component of the E3 ubiquitin ligase CRL5, is essential for retinal layering and function. RBX2 regulates the final cell position of rod bipolar cells, cone photoreceptors, and Muller glia. Our data indicate that sustained Reelin/DAB1 signaling, triggered by depletion of RBX2 or SOCS7 -a CRL5 substrate adaptor known to recruit DAB1- causes rod bipolar cell misposition...
January 18, 2018: Development
Aude Molinard-Chenu, Alexandre Dayer
BACKGROUND: Alterations in early steps of cortical circuit assembly are thought to play a critical role in vulnerability to schizophrenia (SZ), but the pathogenic impact of SZ-risk mutations on corticogenesis remains to be determined. DiGeorge syndrome critical region 2 (DGCR2) is located in the 22q11.2 locus, whose deletion is a major risk factor for SZ. Moreover, exome sequencing of individuals with idiopathic SZ identified a rare missense mutation in DGCR2, further suggesting that DGCR2 is involved in SZ...
November 21, 2017: Biological Psychiatry
Markus Schulze, Christ Violonchi, Stefan Swoboda, Tobias Welz, Eugen Kerkhoff, Sabine Hoja, Susanne Brüggemann, Johann Simbürger, Jörg Reinders, Markus J Riemenschneider
Glioblastoma (GBM) represents the most common and most malignant type of primary brain tumor and significantly contributes to cancer morbidity and mortality. Invasion into the healthy brain parenchyma is a major feature of glioblastoma aggressiveness. Reelin (RELN) is a large secreted extracellular matrix glycoprotein that regulates neuronal migration and positioning in the developing brain and sustains functionality in the adult brain. We here show that both RELN and its main downstream effector DAB1 are silenced in glioblastoma as compared to non-neoplastic tissue and mRNA expression is inversely correlated with malignancy grade...
December 8, 2017: Brain Pathology
Shaobo Wang, Bianka Brunne, Shanting Zhao, Xuejun Chai, Jiawei Li, Jeremie Lau, Antonio Virgilio Failla, Bernd Zobiak, Mirjam Sibbe, Gary L Westbrook, David Lutz, Michael Frotscher
Reelin controls neuronal migration and layer formation. Previous studies in reeler mice deficient in Reelin focused on the result of the developmental process in fixed tissue sections. It has remained unclear whether Reelin affects the migratory process, migration directionality or migrating neurons guided by the radial glial scaffold. Moreover, Reelin has been regarded as an attractive signal, since newly generated neurons migrate toward the Reelin-containing marginal zone. Conversely, Reelin might be a stop signal, since migrating neurons in reeler, but not in wild-type mice, invade the marginal zone...
November 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
David Lutz, Ahmed Sharaf, Dagmar Drexler, Hardeep Kataria, Gerrit Wolters-Eisfeld, Bianka Brunne, Ralf Kleene, Gabriele Loers, Michael Frotscher, Melitta Schachner
The cell adhesion molecule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80)...
November 10, 2017: Scientific Reports
Pieter Vancamp, Marie-Anne Deprez, Michiel Remmerie, Veerle M Darras
Thyroid hormones (THs) are essential for establishing layered brain structures, a process called corticogenesis, by acting on transcriptional activity of numerous genes. In humans, deficiency of the monocarboxylate transporter 8 (MCT8), involved in cellular uptake of THs before their action, results in severe neurological abnormalities, known as the Allan-Herndon-Dudley syndrome. While the brain lesions predominantly originate prenatally, it remains unclear how and when exactly MCT8 dysfunction affects cellular processes crucial for corticogenesis...
November 29, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Helge Hass, Friederike Kipkeew, Aziz Gauhar, Elisabeth Bouché, Petra May, Jens Timmer, Hans H Bock
Reelin is a large glycoprotein with a dual role in the mammalian brain. It regulates the positioning and differentiation of postmitotic neurons during brain development and modulates neurotransmission and memory formation in the adult brain. Alterations in the Reelin signaling pathway have been described in different psychiatric disorders. Reelin mainly signals by binding to the lipoprotein receptors Vldlr and ApoER2, which induces tyrosine phosphorylation of the adaptor protein Dab1 mediated by Src family kinases (SFKs)...
2017: PloS One
Bin Zhang, Weiwei Wang, Zhenjie Zhang, Yaling Hu, Fan Meng, Fan Wang, Huifang Lou, Liya Zhu, Roseline Godbout, Shumin Duan, Zhihua Gao
Multipolar-to-bipolar transition (MBT) is crucial for the neuronal migration and positioning in the neocortex. Reelin-Disabled-1 (Dab1) signaling plays a pivotal role in neuronal migration, yet how Dab1 coordinatively regulates downstream molecules to affect MBT remains unclear. We have previously found that alternative splicing produces multiple Dab1 isoforms with different tyrosine motifs and differential ability to recruit downstream effectors. Here, we report that splicing of Dab1 exons 7 and 8 and 9bc dynamically regulates the inclusion and activities of Dab1 tyrosine motifs in the neocortex...
August 22, 2017: Cerebral Cortex
Takao Kohno
Reelin is a large secreted glycoprotein that regulates embryonic neuronal lamination and adult synaptic function. Secreted Reelin binds to lipoprotein receptors expressed on neurons. The Reelin-receptor interaction induces phosphorylation of an intracellular adaptor protein Dab1, which is required for normal embryonic brain development and adult brain functions. It has been suggested that Reelin hypofunction plays a role in the pathogenesis of several neuropsychiatric diseases, such as schizophrenia, autism, and Alzheimer's disease...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Marissa Blume, Fuduki Inoguchi, Taku Sugiyama, Yuji Owada, Noriko Osumi, Yoshinari Aimi, Kosuke Taki, Yu Katsuyama
The hippocampal formation (HF) is morphologically and functionally distinguishable into the subdivisions, such as the dentate gyrus (DG), subiculum, and Ammon's horn. The Ammon's horn is further divided into the CA (Cornu Ammonis)1, CA2, and CA3. The Reelin-Dab1 signal is essential for the morphogenesis of the mammalian brain. In the neocortex of Reelin-Dab1 signal mutants the laminar pattern of the neurons is disrupted along the radial axis. Morphological abnormalities in the HF of the Reelin-Dab1 mutants were known, but how these abnormalities appear during development had not been extensively studied...
September 25, 2017: Development, Growth & Differentiation
Nina Sarah Gowert, Irena Krüger, Meike Klier, Lili Donner, Friederike Kipkeew, Michael Gliem, Nicholas J Bradshaw, David Lutz, Sabrina Köber, Harald Langer, Sebastian Jander, Kerstin Jurk, Michael Frotscher, Carsten Korth, Hans H Bock, Margitta Elvers
Reelin is a secreted glycoprotein and essential for brain development and plasticity. Recent studies provide evidence that Reelin modifies platelet actin cytoskeletal dynamics. In this study we sought to dissect the contribution of Reelin in arterial thrombus formation. Here we analyzed the impact of Reelin in arterial thrombosis ex vivo and in vivo using Reelin deficient (reeler) and wildtype mice. We found that Reelin is secreted upon platelet activation and mediates signaling via glycoprotein (GP)Ib, the amyloid precursor protein (APP) and apolipoprotein E receptor 2 (ApoER2) to induce activation of Akt, extracellular signal-regulated kinase (Erk), SYK and Phospholipase Cγ2...
December 2017: Cellular Signalling
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