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1.
Stem Cell Res Ther ; 10(1): 209, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311585

RESUMO

BACKGROUND: Definitive treatment strategies for bisphosphonate-related osteonecrosis of the jaw (BRONJ) have not been developed. Cell-based therapy is an attractive treatment method for intractable diseases in the medical and dental fields; however, approval has been challenging in dentistry. Recently, we developed quality- and quantity (QQ)-controlled peripheral blood mononuclear cells (PBMNCs) that have anti-inflammatory and pro-angiogenesis effects. The aim of this study was to investigate the effects of QQ-controlled PBMNC transplantation on BRONJ-like lesions in mice. METHODS: To create high-prevalence BRONJ-like lesions, cyclophosphamide (CY) and zoledronate (ZA) were used with tooth extraction. Drug treatment was performed for 5 weeks. QQ-controlled PBMNC transplantation was performed immediately following tooth extraction of both maxillary first molars at 3 weeks after drug administration. Mice were euthanized at 2 weeks post-extraction. Histomorphometric and immunohistochemical analyses, microcomputed tomography assessment, and quantitative polymerase chain reaction evaluation were conducted using maxillae and long bones. RESULTS: ZA effects on long bones were noted, regardless of CY. Severely inhibited osseous and soft tissue wound healing of tooth extraction sockets was induced by CY/ZA combination therapy, which was diagnosed as BRONJ-like lesions. QQ-controlled PBMNC transplantation reduced BRONJ-like lesions by improving soft tissue healing with increased M1 and M2 macrophages and enhanced neovascularization in the connective tissue of tooth extraction sockets. QQ-controlled PBMNC transplantation also reduced inflammation by decreasing polymorphonuclear cells and TNF-α expression in the tooth extraction sockets. Additionally, QQ-controlled PBMNC transplantation partially improved osseous healing of tooth extraction sockets. Interestingly, only 20,000 QQ-controlled PBMNCs per mouse induced these transplantation effects. QQ-controlled PBMNC transplantation did not affect the systemic microenvironment. CONCLUSIONS: Our findings suggest that transplantation of a small amount of QQ-controlled PBMNCs may become novel therapeutic or prevention strategies for BRONJ without any adverse side effects.

2.
J Comp Neurol ; 527(10): 1577-1597, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30636008

RESUMO

During development of the mammalian cerebral neocortex, postmitotic excitatory neurons migrate toward the outermost region of the neocortex. We previously reported that this outermost region is composed of densely packed relatively immature neurons; we named this region, which is observed during the late stage of mouse neocortical development, the "primitive cortical zone (PCZ)." Here, we report that postmigratory immature neurons spend about 1-1.5 days in the PCZ. An electron microscopic analysis showed that the neurons in the PCZ tend to be in direct contact with each other, mostly in a radial direction, forming "primitive neuronal clusters" with a height of 3-7 cells and a width of 1-2 cells. A time-course analysis of fluorescently labeled neurons revealed that the neurons took their positions within the primitive clusters in an inside-out manner. The neurons initially participated in the superficial part of the clusters, gradually shifted their relative positions downward, and then left the clusters at the bottom of this structure. GABAergic inhibitory interneurons were also found within the primitive clusters in the developing mouse neocortex, suggesting that some clusters are composed of both excitatory neurons and inhibitory interneurons. Similar clusters were also observed in the outermost region of embryonic day (E) 78 cynomolgus monkey occipital cortex and 23 gestational week (GW) human neocortices. In the primate neocortices, including human, the presumptive primitive clusters seemed to expand in the radial direction more than that observed in mice, which might contribute to the functional integrity of the primate neocortex.

4.
J Neurosci ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504273

RESUMO

The actin cytoskeleton is crucial for neuronal migration in the mammalian developing cerebral cortex. The adaptor protein Drebrin-like (Dbnl) plays important roles in reorganization of the actin cytoskeleton, dendrite formation, and endocytosis by interacting with F-actin, cobl, and dynamin. While Dbnl is known to be expressed in the brain, the functions of this molecule during brain development are largely unknown. In this study, to examine the roles of Dbnl in the developing cerebral cortex, we conducted experiments using of both sexes mice with knockdown of Dbnl, effected by in utero electroporation, in the migrating neurons of the embryonic cortex. Time-lapse imaging of the Dbnl-knockdown neurons revealed that the presence of Dbnl is a prerequisite for appropriate formation of processes in the multipolar neurons in the multipolar cell accumulation zone (MAZ) or the deep part of the subventricular zone (SVZ), and for neuronal polarization and entry into the cortical plate. We found that Dbnl knockdown decreased the amount of N-cadherin protein expressed on the plasma membrane of the cortical neurons. The defect in neuronal migration caused by Dbnl knockdown was rescued by moderate overexpression of N-cadherin and αN-catenin or by transfection of the phospho-mimic form (Y337E, Y347E), but not the phospho-resistant form (Y337F, Y347F), of Dbnl. These results suggest that Dbnl controls neuronal migration, neuronal multipolar morphology, and cell polarity in the developing cerebral cortex via regulating N-cadherin expression.SIGNIFICANCE STATEMENTDisruption of neuronal migration can cause neuronal disorders such as lissencephaly and subcortical band heterotopia. During cerebral cortical development, the actin cytoskeleton plays a key role in neuronal migration, however, the mechanisms of regulation of neuronal migration by the actin cytoskeleton still remain unclear. Herein, we report that the novel protein Dbnl, an actin-binding protein, controls multiple events during neuronal migration in the developing mouse cerebral cortex. We also showed that this regulation is mediated by phosphorylation of Dbnl at tyrosine residues 337 and 347 and αN-catenin/N-cadherin, suggesting that the Dbnl-αN-catenin/N-cadherin pathway is important for neuronal migration in the developing cortex.

5.
Bone ; 112: 177-186, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29729428

RESUMO

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) worsens oral health-related quality of life. Most BRONJ occurs in multiple myeloma or metastatic breast cancer patients treated with bisphosphonate/chemotherapeutic combination therapies. Cyclophosphamide (CY), an alkylating chemotherapeutic drug, is used to treat multiple myeloma, although its use has been recently reduced. The aim of this study was to clarify the effects of CY dose on tooth extraction socket healing when CY is used with or without bisphosphonate in mice. Low-dose CY (50 mg/kg; CY-L), moderate-dose CY (100 mg/kg; CY-M), high-dose CY (150 mg/kg; CY-H), and bisphosphonate [Zometa (ZA): 0.05 mg/kg] were administered for 7 weeks. Each dose of CY and ZA in combination was also administered for 7 weeks. Both maxillary first molars were extracted at 3 weeks after the initiation of drug administration. Euthanasia was performed at 4 weeks post-extraction. Gross wound healing, microcomputed tomography analysis, histomorphometry, and immunohistochemistry were used to quantitatively evaluate osseous and soft tissue wound healing of tooth extraction sockets. ZA monotherapy induced no BRONJ-like lesions in mice. CY monotherapy rarely induced open wounds, though delayed osseous wound healing occurred in a CY dose-dependent manner. In contrast, CY/ZA combination therapy prevalently induced BRONJ-like lesions with compromised osseous and soft tissue healing in a CY dose-dependent manner. Interestingly, anti-angiogenesis was noted regardless of CY dose and ZA administration, even though only CY-M/ZA and CY-H/ZA combination therapies induced BRONJ-like lesions. Our findings suggest that high-dose CY may be associated with the development of BRONJ following tooth extraction only when CY is used together with ZA. In addition to anti-angiogenesis, other factors may contribute to the pathoetiology of BRONJ.

6.
J Palliat Med ; 21(10): 1494-1498, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29723109

RESUMO

OBJECT: To examine the clinical outcomes of a project to enhance the awareness of community-based palliative care (awareness-enhancing project), focusing on home death and care rates in communities. METHODS: A single-center study on community-based intervention was conducted. The awareness-enhancing project, consisting of three intervention approaches (outreach, palliative care education for community-based medical professionals, and information-sharing tool use), was executed, and changes in the home death rate in the community were examined. RESULTS: The home death rate markedly exceeded the national mean from 2010. In 2012-2013, it was as high as 19.9%, greater than the previous 5.9% (p = 0.001). Through multivariate analysis, the participation of home care physicians and visiting nurses in a palliative care education program, and patients' Palliative Prognostic Index values were identified as factors significantly influencing the home death rate. CONCLUSION: The three intervention approaches time dependently increased the home death rate as a clinical outcome in the community, although they targeted limited areas. These approaches may aid in increasing the number of individuals who die in their homes.

7.
Cereb Cortex ; 28(1): 223-235, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27909010

RESUMO

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex.


Assuntos
Movimento Celular/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Neurônios/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA1 Hipocampal/metabolismo , Córtex Cerebral/citologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Integrinas/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo
8.
Neurochem Res ; 43(1): 238-244, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29185180

RESUMO

The diversification of neuronal subtypes during corticogenesis is fundamental to the establishment of the complex cortical structure. Although subtype specification has been assumed to occur in neural progenitor cells, increasing evidence has begun to reveal the plasticity of subtype determination in immature neurons. Here, we summarize recent findings regarding the regulation of subtype specification during later periods of neuronal differentiation, such as the post-mitotic and post-migratory stages. We also discuss thalamocortical axons as an extra-cortical cue that provides information on the subtype determination of immature cortical neurons.


Assuntos
Diferenciação Celular/fisiologia , Córtex Cerebral/citologia , Neurônios/citologia , Células-Tronco/citologia , Animais , Axônios/fisiologia , Linhagem da Célula/fisiologia , Humanos
9.
J Bone Miner Metab ; 36(5): 547-559, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29043461

RESUMO

Osteonecrosis of the jaw (ONJ), which is a rare but severe adverse effect, mainly occurs in oncology patients receiving chemotherapeutic agents and bisphosphonates. However, the combined impact of chemotherapy and bisphosphonates on wound healing after tooth extraction remains unknown. The aim of this study was to determine the precise etiology of ONJ induced by chemotherapy and bisphosphonate combination therapy. Mice received zoledronate (ZA) monotherapy, cyclophosphamide (CY) monotherapy or CY/ZA combination therapy. The maxillary first molars were extracted 3 weeks after the initiation of drug treatment. Moreover, antivascular endothelial growth factor A (VEGFA) monoclonal antibody (mAb) was administered once every 2 days just after tooth extraction for 2 weeks. Soft and hard tissue wound healing was evaluated 2 and 4 weeks post-extraction using histomorphometry, microcomputed tomography and immunohistochemistry. ZA monotherapy did not induce impaired oral wound healing and ONJ-like lesions 2 and 4 weeks post-extraction, respectively. Tooth extraction socket healing worsened with severe anti-angiogenesis by CY monotherapy and CY/ZA combination therapy 2 weeks post-extraction. However, CY monotherapy rarely induced ONJ-like lesions with severe angiogenesis suppression, whereas CY/ZA combination therapy frequently induced ONJ-like lesions with severe angiogenesis inhibition 4 weeks post-extraction. Interestingly, anti-VEGFA mAb therapy delayed osseous wound healing with normal soft tissue wound healing of tooth extraction sockets, although this therapy significantly suppressed blood vessel formation. Our findings suggest that anti-angiogenesis alone is not the main cause of ONJ-like lesions induced by CY/ZA combination therapy. The combination of suppressed osteoclasts and anti-angiogenesis, in addition to other risk factors such as chemotherapy, may contribute to the development of ONJ.


Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/uso terapêutico , Difosfonatos/farmacologia , Extração Dentária , Alvéolo Dental/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Cicatrização , Inibidores da Angiogênese/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/administração & dosagem , Quimioterapia Combinada , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Alvéolo Dental/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Cicatrização/efeitos dos fármacos , Microtomografia por Raio-X , Ácido Zoledrônico
10.
J Bone Miner Res ; 33(1): 154-166, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28902422

RESUMO

The precise pathoetiology and effective treatment strategies for bisphosphonate-related osteonecrosis of the jaw (BRONJ) remain unknown. Transplantation of noncultured stromal vascular fraction (SVF) cells has been shown to be a useful method for regenerative medicine in place of stem cell therapy. This study investigated the effects of noncultured SVF transplantation on tooth extraction socket healing in mice. Both chemotherapeutic/bisphosphonate combination therapy for 7 weeks and tooth extraction of maxillary first molars at 3 weeks after drug administration were performed using female C57BL/6J mice. Osseous and soft tissue wound healing were validated at 4 weeks postextraction using gross wound healing and histomorphometry. Here, we created a new animal model of high-prevalence ONJ-like lesions that mimic human progression, because human ONJ mainly occurs in female patients taking both chemotherapeutic and bisphosphonate following tooth extraction. Moreover, mice with chemotherapeutic and bisphosphonate combination therapy for 5 weeks received SVF transplantation just after tooth extraction at 3 weeks post-drug administration. Euthanasia was performed at 2 weeks postextraction to assess the transplantation effects on wound healing using gross wound healing, histomorphometry, immunohistomorphometry, quantitative real-time polymerase chain reaction, and microcomputed tomography. We showed that systemic transplantation of noncultured SVF cells ameliorates ONJ-like lesions by improving both osseous and soft tissue healing of tooth extraction sockets. SVF therapy significantly increased blood vessels and the ratio of M2/M1 macrophages. In addition, SVF transplantation reduced the increases in tartrate-resistant acid phosphatase-positive (TRAP+ ) mononuclear cells (MNCs) and nonattached osteoclasts from the bone surface, which were significantly detected in the connective tissue of tooth extraction sockets and bone marrow by chemotherapeutic/bisphosphonate combination therapy. Our findings suggest that transplantation of noncultured SVF cells is a suitable treatment for BRONJ. Abnormal TRAP+ MNCs and nonattached osteoclasts in systemic and local environments may contribute to the development of BRONJ. © 2017 American Society for Bone and Mineral Research.

11.
Stem Cells Transl Med ; 7(2): 173-179, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29274116

RESUMO

Clinical application of induced pluripotent stem cells (iPS) in autologous settings has just begun. To overcome the high time and cost barriers in the individual production of autologous iPS, the use of allogeneic iPS with a homozygous human leukocyte antigen (HLA) haplotype (HLA-homo HP) has been proposed. Cord blood transplantation (CBT) is a suitable model for evaluating the allogeneic immunogenicity of iPS transplantation from HLA-homo donors. We analyzed 1,374 Japanese single cord blood transplant pairs who were retrospectively typed as HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. Among these, six pairs with donor HLA homo-patient-HLA hetero (homo-hetero) were found, all of which showed favorable neutrophil engraftment. Multivariate analysis revealed a significantly elevated engraftment risk (HR = 1.59) compared with hetero-hetero pairs with HLA 1-2 locus mismatch (789 pts) and comparative risk (HR = 1.23) compared with hetero-hetero pairs with 0 mismatch (104 pts). These results for CBT with HLA-homo HP cord blood carry an important implication, namely the possibility that HLA-homo iPS transplantation results in favorable engraftment. Furthermore, we obtained detailed information on HLA alleles and haplotypes of HLA-homo. All donor HLA-homo HPs had a common specific ethnicity and high conservation of the HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA-homo HP, and another non-shared patient HP was mismatched with 1 to 4 HLA alleles of HLA-A, -B, -C, and -DRB1 loci in the GVH direction. These findings indicate that patients possessing a single common HLA haplotype have a higher chance of yielding HLA-homo iPS. Stem Cells Translational Medicine 2018;7:173-179.

12.
J Oral Sci ; 59(4): 533-539, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29279567

RESUMO

The aim of this study was to develop an effective method for cleaning implant abutments made by computer-aided design and computer-aided manufacturing techniques and to investigate the effect of decontamination in vitro. Briefly, a newly developed reagent (PK) and/or vacuum plasma (Plasma) were used to clean the surfaces of zirconia disks, and the effects of this decontamination were evaluated by X-ray photoelectron spectroscopy. Human gingival fibroblasts (HGFs) were cultured on sample disks for 6, 24, and 48 h. We evaluated cell attachment and gene expression of the acute inflammatory cytokines interleukin-6 and vascular endothelial growth factor A, and type 1 collagen. In the PK and PK+Plasma groups, surface contaminants were reduced by washing. In addition, HGF attachments was increased in the PK and PK+Plasma groups. Gene expressions of interleukin-6 and vascular endothelial growth factor A were lower at 6 h. Gene expression of type 1 collagen was increased at all time points after seeding. These results suggest that decontamination of implant abutment surfaces is important in initial HGF attachment and may improve the biological seal of peri-implant soft tissue.


Assuntos
Dente Suporte , Expressão Gênica , Gengiva/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Gengiva/citologia , Humanos , Mediadores da Inflamação/metabolismo , Espectroscopia Fotoeletrônica , Propriedades de Superfície
13.
Elife ; 62017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29179815

RESUMO

CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, and is characterized by a set of malformations that, on clinical grounds, were historically postulated to arise from defects in neural crest formation during embryogenesis. To better delineate neural crest defects in CHARGE syndrome, we generated induced pluripotent stem cells (iPSCs) from two patients with typical syndrome manifestations, and characterized neural crest cells differentiated in vitro from these iPSCs (iPSC-NCCs). We found that expression of genes associated with cell migration was altered in CHARGE iPSC-NCCs compared to control iPSC-NCCs. Consistently, CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation in ovo revealed overall defective migratory activity in the chick embryo. These results support the historical inference that CHARGE syndrome patients exhibit defects in neural crest migration, and provide the first successful application of patient-derived iPSCs in modeling craniofacial disorders.


Assuntos
Síndrome CHARGE/fisiopatologia , Movimento Celular , Crista Neural/fisiologia , Animais , Síndrome CHARGE/genética , Diferenciação Celular , Células Cultivadas , Embrião de Galinha , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Proteínas Mutantes/genética , Mutação
14.
Dent Traumatol ; 33(6): 421-426, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28965361

RESUMO

There appears to be much confusion or misinformation worldwide regarding mouthguards and their use in sports. In an effort to clarify where the international dental community stands on mouthguards and mouthguard research, the workshop looked at some important questions. The goal was to one day formulate consensus statements related to these questions, which will be based on current scientific evidence-based research, to motivate the international community of the importance of dentally fitted laminated mouthguards and the wearing of them by athletes of all sports. There are only five sports in the United States that require the use of mouthguards. If, through workshops such as this, the importance of wearing dentally fitted laminated mouthguards can be demonstrated, then more sports may require their athletes to wear them.


Assuntos
Traumatismos em Atletas/prevenção & controle , Traumatismos Maxilofaciais/prevenção & controle , Protetores Bucais/estatística & dados numéricos , Esportes , Congressos como Assunto , Humanos
15.
EBioMedicine ; 24: 102-115, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28928015

RESUMO

Cytoplasmic aggregation of fused in sarcoma (FUS) is detected in brain regions affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which compose the disease spectrum, FUS proteinopathy. To understand the pathomechanism of ALS-FTD-associated FUS, we examined the behavior and cellular properties of an ALS mouse model overexpressing FUS with nuclear localization signal deletion. Mutant FUS transgenic mice showed hyperactivity, social interactional deficits, and impaired fear memory retrieval, all of which are compatible with FTD phenotypes. Histological analyses showed decreased dendritic spine and synaptic density in the frontal cortex before neuronal loss. Examination of cultured cells confirmed that mutant but not wild-type FUS was associated with decreased dendritic growth, mRNA levels, and protein synthesis in dendrites. These data suggest that cytoplasmic FUS aggregates impair dendritic mRNA trafficking and translation, in turn leading to dendritic homeostasis disruption and the development of FTD phenotypes.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Demência Frontotemporal/metabolismo , RNA Mensageiro/metabolismo , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Esclerose Amiotrófica Lateral/genética , Animais , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Demência Frontotemporal/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Neurônios/metabolismo , Biossíntese de Proteínas
16.
PLoS One ; 12(8): e0183497, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28820910

RESUMO

The basic helix-loop-helix (bHLH) transcription factors exert multiple functions in mammalian cerebral cortex development. The aryl hydrocarbon receptor (AhR), a member of the bHLH-Per-Arnt-Sim subfamily, is a ligand-activated transcription factor reported to regulate nervous system development in both invertebrates and vertebrates, but the functions that AhR signaling pathway may have for mammalian cerebral cortex development remains elusive. Although the endogenous ligand involved in brain developmental process has not been identified, the environmental pollutant dioxin potently binds AhR and induces abnormalities in higher brain function of laboratory animals. Thus, we studied how activation of AhR signaling influences cortical development in mice. To this end, we produced mice expressing either constitutively active-AhR (CA-AhR), which has the capacity for ligand-independent activation of downstream genes, or AhR, which requires its ligands for activation. In brief, CA-AhR-expressing plasmid and AhR-expressing plasmid were each transfected into neural stems cells in the developing cerebrum by in utero electroporation on embryonic day 14.5. On postnatal day 14, mice transfected in utero with CA-AhR, but not those transfected with AhR, exhibited drastically reduced dendritic arborization of layer II/III pyramidal neurons and impaired neuronal positioning in the developing somatosensory cortex. The effects of CA-AhR were observed for dendrite development but not for the commissural fiber projection, suggesting a preferential influence on dendrites. The present results indicate that over-activation of AhR perturbs neuronal migration and morphological development in mammalian cortex, supporting previous observations of impaired dendritic structure, cortical dysgenesis, and behavioral abnormalities following perinatal dioxin exposure.


Assuntos
Dendritos , Células Piramidais/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Animais , Camundongos , Camundongos Endogâmicos C57BL
17.
Brain Struct Funct ; 222(9): 4283-4291, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28836069

RESUMO

Mutations of PAFAH1B1 cause classical lissencephaly in humans. In addition, duplications and triplications of PAFAH1B1 are found in individuals with intellectual disability and other neurological disorders suggesting that proper brain development is highly sensitive to the PAFAH1B1 dosage. To examine the effect of PAFAH1B1 over-dosage in neural development, especially in migration of neurons and layer formation during cerebral cortical development, we overexpressed Pafah1b1 in migrating neurons in the mouse embryonic cortex using in utero electroporation. Enhanced expression of Pafah1b1 in radially-migrating neurons resulted in their over-migration into the marginal zone. Neurons that invaded the marginal zone were oriented abnormally. Layer distribution of Pafaha1b1-overexpressing neurons shifted more superficially than control neurons. Some of the Pafaha1b1-overexpressing future layer 4 neurons changed their positions to layers 2/3. Furthermore, they also changed their layer marker expression from layer 4 to layers 2/3. These results suggest that overexpression of Pafah1b1 affects the migration of neurons and disrupts layer formation in the developing cerebral cortex, and further support the idea that appropriate dosage of Pafah1b1 is crucial for the proper development of the brain.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Movimento Celular/fisiologia , Córtex Cerebral/citologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/fisiologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fatores de Transcrição/metabolismo
18.
Adv Exp Med Biol ; 977: 199-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28685446

RESUMO

Aging often results in a decline in cognitive function, related to alterations in the prefrontal cortex (PFC) activation. Maintenance of this function in an aging society is an important issue. Some practices/drills, moderate exercise, mastication, and a cognitive task itself could enhance cognitive function. In this validation study, before evaluating the effects of some drills on the elderly, we examined the neural substrate of blood oxygenation changes by the use of four cognitive tasks and fNIRS. Seven healthy volunteers (mean age 25.3 years) participated in this study. Each task session was designed in a block manner; 4 periods of rests (30 s) and 3 blocks of four tasks (30 s). The tasks used were: a computerized Stroop test, a Wisconsin Card Sorting Test, a Sternberg working memory paradigm, and a semantic verbal fluency task. The findings of the study are that all four tasks activated PFC to some extent, without laterality except for the verbal fluency task. The results confirm that NIRS is suitable for measurement of blood oxygenation changes in frontal brain areas that are associated with all four cognitive tasks.


Assuntos
Circulação Cerebrovascular/fisiologia , Cognição/fisiologia , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Córtex Pré-Frontal/irrigação sanguínea , Córtex Pré-Frontal/metabolismo , Adulto , Mapeamento Encefálico/métodos , Lateralidade Funcional/fisiologia , Humanos , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Semântica , Espectroscopia de Luz Próxima ao Infravermelho , Fala/fisiologia , Adulto Jovem
19.
Front Cell Dev Biol ; 5: 40, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28507985

RESUMO

The mammalian cerebral neocortex has a well-organized laminar structure, achieved by the highly coordinated control of neuronal migration. During cortical development, excitatory neurons born near the lateral ventricle migrate radially to reach their final positions to form the cortical plate. During this process, dynamic changes are observed in the morphologies and migration modes, including multipolar migration, locomotion, and terminal translocation, of the newborn neurons. Disruption of these migration processes can result in neuronal disorders such as lissencephaly and periventricular heterotopia. The extracellular protein, Reelin, mainly secreted by the Cajal-Retzius neurons in the marginal zone during development, plays a crucial role in the neuronal migration and neocortical lamination. Reelin signaling, which exerts essential roles in the formation of the layered neocortex, is triggered by the binding of Reelin to its receptors, ApoER2 and VLDLR, followed by phosphorylation of the Dab1 adaptor protein. Accumulating evidence suggests that Reelin signaling controls multiple steps of neuronal migration, including the transition from multipolar to bipolar neurons, terminal translocation, and termination of migration beneath the marginal zone. In addition, it has been shown that ectopically expressed Reelin can cause neuronal aggregation via an N-cadherin-mediated manner. This review attempts to summarize our knowledge of the roles played by Reelin in neuronal migration and the underlying mechanisms.

20.
JCI Insight ; 2(10)2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28515367

RESUMO

Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.

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