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1.
Nihon Shokakibyo Gakkai Zasshi ; 120(3): 269-275, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-36908146

RESUMO

This is a case report of fascioliasis that progressed from the hepatic to the biliary phases over 2 years. A woman in her late 60s ate Zingiber mioga from the field, which was followed by abdominal pain that occurred 1 month later. Although CT and MRI studies revealed an increase in blood eosinophils as well as multiple hepatic nodules, they vanished quickly. After 2 years, an MRCP study revealed multiple flat lesions, which were diagnosed as adult fascioliasis. Definitive diagnosis was provided by enzyme-labeled antibody method using fasciola-specific antigen. Triclabendazole was administered once to complete the treatment.


Assuntos
Anti-Helmínticos , Fasciolíase , Feminino , Humanos , Fasciolíase/diagnóstico , Fasciolíase/tratamento farmacológico , Fasciolíase/patologia , Anti-Helmínticos/uso terapêutico , Benzimidazóis/uso terapêutico , Triclabendazol/uso terapêutico
2.
Pathol Int ; 72(5): 273-282, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35234319

RESUMO

Bronchiolar adenoma (BA) is a rare benign lung tumor that shows proliferation of bland bronchiolar-type epithelium containing a continuous layer of basal cells. This tumor entity has been newly added to the recent World Health Organization (WHO) classification 5th edition. This entity encompasses a spectrum of lesions: the classic ciliated muconodular papillary tumor (CMPT) and the non-classic CMPT. Although BA is reported to have driver mutations including BRAF V600E, EGFR, and KRAS, the molecular profile of BA is still incompletely understood. Five resected BAs at our institutions were analyzed. The BA lesions were subdivided into two groups: three proximal-type BAs and two distal-type BAs. NRAS codon 12/13 mutation and EML4 exon 20-ALK exon 20 fusion were found in two of the three proximal-types. BRAF V600E mutation was found in one of the two distal-types. Two cases coexisted with lung adenocarcinoma, with EGFR exon 19 deletion and KRAS mutation, respectively. No recurrence was observed at a median of 12 months (range 2-84 months) of follow-up. BA has uncommon variants of mutation seen in lung adenocarcinoma. NRAS mutation and ALK fusion partner has not been reported previously. The present cases may reinforce the distinctive biology of BA from lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Adenoma , Neoplasias Pulmonares , Adenoma/genética , Adenoma/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Proteína Tirosina Quinases/genética
3.
J Cell Physiol ; 236(10): 7134-7143, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33694168

RESUMO

The neurovascular unit (NVU) consists of neurons, glial cells, microvascular cells, and extracellular matrix, and is involved in a variety of physiological and pathological processes in the central nervous system (CNS). Within the NVU, the microvascular endothelial cells and pericytes principally contribute to maintaining the integrity of the blood-brain barrier (BBB). Various types of cells are connected to each other in the NVU by diverse cell adhesion molecules, of which claudin-5 (CLDN5) is by far the most abundantly expressed tight-junction protein in brain microvascular endothelial cells and absolutely required for the maintenance of the BBB. This review highlights recent progress in understanding the region-specific regulation and dysregulation of CLDN5 expression in CNS health and disorders. We also discuss how CLDN5 expression is regionally disrupted within the NVU. In addition, we focus on the link between cell adhesion and transcription factor signalings and describe the possible involvement of CLDN5-adhesion signaling in brain health and disorders.


Assuntos
Barreira Hematoencefálica/metabolismo , Encefalopatias/metabolismo , Claudina-5/metabolismo , Células Endoteliais/metabolismo , Transdução de Sinais , Junções Íntimas/metabolismo , Animais , Barreira Hematoencefálica/patologia , Encefalopatias/genética , Encefalopatias/patologia , Claudina-5/genética , Células Endoteliais/patologia , Regulação da Expressão Gênica , Humanos , Junções Íntimas/genética , Junções Íntimas/patologia
4.
Pathol Int ; 71(1): 96-101, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33079423

RESUMO

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed-Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5- , CD15+ , CD20- , CD30+ , PAX5+ , Bob.1- , Oct2- and EBER+ . The MCL component expressed cyclin D1 and SOX11, whereas cyclin D1 and SOX11 expressions were reduced and lost, respectively, in HRS-like cells. Polymerase chain reaction results showed a single clonal rearrangement of the IGH gene in MCL and cHL-like components. CCND1 break apart fluorescence in situ hybridization showed split signals in both MCL and HRS-like cells, suggesting that MCL and cHL-like components were clonally related. Acquisition of p53 expression and Epstein-Barr virus (EBV)-positivity was seen in HRS-like cells. The patient died of disease progression with elevated hepatobiliary enzymes. The autopsy showed both MCL and cHL-like components around the bile ducts, splenic white pulp and bone marrow. The two components were phenotypically distinct, but genetically related, suggesting that transformation of MCL to HRS-like cells during the course of MCL in association with EBV infection.


Assuntos
Linfoma de Célula do Manto , Idoso , Autoenxertos/anormalidades , Biomarcadores Tumorais/análise , Ciclina D1/análise , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/patologia , Humanos , Hibridização in Situ Fluorescente , Linfonodos/patologia , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/patologia , Masculino , Células de Reed-Sternberg/citologia , Proteína Supressora de Tumor p53/análise
5.
Int J Clin Oncol ; 26(12): 2303-2309, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34537890

RESUMO

BACKGROUND: Population-based prostate-specific antigen (PSA) screening is effective for reducing prostate cancer (PCa)-related mortality rates. In this study, we assessed biopsy-proven maximum cancer core length (MCCL) and maximum cancer diameter on magnetic resonance imaging (MRI; MCDM) in prostate biopsy and multiparametric MRI (mp-MRI) by PCa detection. METHODS: We retrospectively assessed 214 male PCa patients and 187 PCa patients with Prostate Imaging Reporting and Data System version 2 (PI-RADS) category 3-5 lesions in pre-biopsy mp-MRI and targeted biopsy characteristics. The mean biopsy-proven MCCL and MCDM were compared among three PSA screening groups, namely the population-based PSA screening (PBS), opportunistic PSA screening (OPS), and symptomatic outpatient PSA examination (SOP) groups. RESULTS: The median age and PSA value of the 214 participants were 75 years and 7.9 ng/mL, respectively. In the PBS, OPS, and SOP groups, the median ages were 73, 76, and 76 years, respectively (p = 0.046); PSA values were 7.2, 9.5, and 11.5 ng/mL, respectively (p < 0.001); and biopsy-proven MCCL and MCDM were significantly increased to 7, 10, and 14 mm (p < 0.001) and to 11, 15, and 17 mm (p < 0.001), respectively. In the 187 PCa patients with PI-RADS category 3-5 lesions on mp-MRI, MCDM were 11, 14, and 17 mm (p < 0.001), respectively. CONCLUSIONS: The biopsy-proven MCCL and MCDM were significantly smaller in the PBS and OPS groups than in the SOP group, which suggests that PSA screening detected PCa earlier than in symptomatic patients. PSA screening with MRI could objectively lead to earlier diagnosis based on tumor size.


Assuntos
Antígenos de Neoplasias , Proteínas de Neoplasias , Antígeno Prostático Específico , Neoplasias da Próstata , Fatores Etários , Detecção Precoce de Câncer , Proteínas Ligadas por GPI , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Neoplasias da Próstata/diagnóstico , Estudos Retrospectivos
6.
Int J Mol Sci ; 22(1)2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383868

RESUMO

We previously reported that site-selective claudin-5 (CLDN5) breakdown and protein kinase A (PKA) activation are observed in brain microvessels of schizophrenia, but the underlying molecular basis remains unknown. The 5-HT1 receptors decline the intracellular cAMP levels and inactivate the major downstream PKA, and the 5-HT1A receptor is a promising target for schizophrenia. Therefore, we elucidated the involvement of serotonin/5-HT1A signaling in the endothelial CLDN5 expression. We demonstrate, by immunohistochemistry using post-mortem human brain tissue, that the 5-HT1A receptor is expressed in brain microvascular endothelial cells (BMVECs) and mural cells of the normal prefrontal cortex (PFC) gray matter. We also show that PKA is aberrantly activated not only in BMVECs but also in mural cells of the schizophrenic PFC. We subsequently revealed that the endothelial cell-pericyte tube-like structure was formed in a novel two-dimensional co-culture of human primary BMVECs and a human brain-derived pericyte cell line, in both of which the 5-HT1A receptor was expressed. Furthermore, we disclose that the serotonin/5-HT1A signaling enhances endothelial CLDN5 expression in BMVECs under two-dimensional co-culture conditions. Our findings provide novel insights into the physiological and pathological significance of serotonin/5-HT1A signaling in the region-specific regulation of the blood-brain barrier.


Assuntos
Claudina-5/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Acoplamento Neurovascular , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Biomarcadores , Encéfalo/metabolismo , Comunicação Celular , Claudina-5/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Imunofluorescência , Humanos , Pericitos/patologia
7.
Gan To Kagaku Ryoho ; 47(4): 652-654, 2020 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-32389973

RESUMO

Screening colorectal endoscopy revealed a 5mm rectal neuroendocrine tumor(NET: G1)in a 72-year-old man. Endoscopic mucosal resection(EMR)was performed, and the histopathological examination demonstrated lymphatic and vessel invasion with a possible positive vertical margin. Therefore, we performed laparoscopic low anterior resection, lymphadenectomy, and ileostomy as additional surgical resections. No residual tumor was found in the specimen, but 3 metastatic lymph nodes were identified. The rate of lymph node metastasis in rectal NETs of diameter<10mm is low, and additional surgery can reduce the patient's quality of life affected due to impaired anorectal function. However, in the Japanese guidelines for NET, additional surgery is adopted in cases with high-risk factors for lymph node metastasis. Therefore, it is necessary to select between additional surgery and careful follow-upfor rectal NETs of diameter<10mm with high-risk factors because of possible lymph node metastasis.


Assuntos
Tumores Neuroendócrinos , Neoplasias Retais , Idoso , Humanos , Excisão de Linfonodo , Linfonodos , Metástase Linfática , Masculino , Tumores Neuroendócrinos/cirurgia , Qualidade de Vida , Neoplasias Retais/cirurgia , Estudos Retrospectivos
8.
Hippocampus ; 29(6): 539-549, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30365199

RESUMO

Neural progenitors acquire GFAP expression during the perinatal period and continue to generate granule cells (GCs) in the hippocampal dentate gyrus throughout adulthood. Cellular characteristics of GFAP+ progenitor-derived late-born GCs in comparison with early-born GCs remain unknown. Using genetic fate mapping in mice, we show that early- and late-born GCs are concentrated in the outer and inner side of the GC layer, respectively. We then identify that a nuclear orphan receptor Nr4A2 is preferentially expressed by early-born GCs. Nr4a2 expression is dynamically regulated in response to restraint stress and glucocorticoid levels, indicating that Nr4a2 is a stress-regulated gene in GCs. Acute stress suppresses but chronic stress conversely induces Nr4a2 expression in GCs. The survival of newly generated GCs is impaired by chronic restraint stress and long-term stress after middle age decreases the proportion of late-born GCs in aged mice. Thus, early- and late-born GCs exhibit characteristic anatomical distribution, differential gene expression, and distinct response to environmental stress.


Assuntos
Giro Denteado/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Glucocorticoides/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Neurogênese/fisiologia , Restrição Física , Estresse Fisiológico
9.
J Neurosci ; 34(17): 5788-99, 2014 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-24760839

RESUMO

The olfactory bulb (OB) is one of the two major loci in the mammalian brain where newborn neurons are constantly integrated into the neural circuit during postnatal life. Newborn neurons are generated from neural stem cells in the subventricular zone (SVZ) of the lateral ventricle and migrate to the OB through the rostral migratory stream. The majority of these newborn neurons differentiate into inhibitory interneurons, such as granule cells and periglomerular cells. It has been reported that prolonged supply of newborn neurons leads to continuous addition/turnover of the interneuronal populations and contributes to functional integrity of the OB circuit. However, it is not still clear how and to what extent postnatal-born neurons contribute to OB neural circuit formation, and the functional role of postnatal neurogenesis in odor-related behaviors remains elusive. To address this question, here by using genetic strategies, we first determined the unique integration mode of newly born interneurons during postnatal development of the mouse OB. We then manipulated these interneuron populations and found that continuous postnatal neurogenesis in the SVZ-OB plays pivotal roles in flexible olfactory associative learning and memory.


Assuntos
Aprendizagem por Associação/fisiologia , Rede Nervosa/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Animais , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/fisiologia , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiologia , Interneurônios/citologia , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Rede Nervosa/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurônios/citologia , Odorantes , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento
10.
Abdom Radiol (NY) ; 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39287628

RESUMO

Intracholecystic papillary neoplasm (ICPN) is a rare preinvasive neoplasm of the gallbladder. The lesion typically appears as a polypoid lesion or gallbladder wall thickening. We report a case involving a 40-year-old man with an ICPN that lacked typical polypoid lesions and was difficult to differentiate from adenomyomatosis because of the presence of intramural cysts. Initial contrast-enhanced computed tomography and magnetic resonance imaging showed edematous gallbladder wall thickening. The lumen was constricted and surrounded by a cluster of small cysts that were suspected to be Rokitansky-Aschoff sinuses (RAS). There were also large cysts within the gallbladder wall. No mucosal irregularities or polypoid lesions were observed, and the mucosal continuity was preserved. After antimicrobial therapy, follow-up computed tomography revealed improvement in the thickening of the gallbladder wall; however, the cysts persisted and some had enlarged. The patient underwent laparoscopic cholecystectomy. Pathologically, a tubulopapillary lesion with atypical epithelial cells was observed in the lumen of the gallbladder, extending continuously into the RAS and cysts within the gallbladder wall. High-grade dysplasia was occasionally found, and microscopic foci of invasion were present. ICPN with associated invasive carcinoma was diagnosed. In conclusion, ICPN may not exhibit polypoid lesions or significant wall thickening on imaging. ICPN may present with secondary RAS dilatation, and the presence of large intramural cysts may be helpful in the diagnosis.

11.
JCI Insight ; 8(16)2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37463055

RESUMO

Intestinal mucins play an essential role in the defense against bacterial invasion and the maintenance of gut microbiota, which is instrumental in the regulation of host immune systems; hence, its dysregulation is a hallmark of metabolic disease and intestinal inflammation. However, the mechanism by which intestinal mucins control the gut microbiota as well as disease phenotypes remains nebulous. Herein, we report that N-acetylglucosamine (GlcNAc)-6-O sulfation of O-glycans on intestinal mucins performs a protective role against obesity and intestinal inflammation. Chst4-/- mice, lacking GlcNAc-6-O sulfation of the mucin O-glycans, showed significant weight gain and increased susceptibility to dextran sodium sulfate-induced colitis as well as colitis-associated cancer accompanied by significantly reduced immunoglobulin A (IgA) production caused by an impaired T follicular helper cell-mediated IgA response. Interestingly, the protective effects of GlcNAc-6-O sulfation against obesity and intestinal inflammation depend on the gut microbiota, evidenced by the modulation of the gut microbiota by cohousing or microbiota transplantation reversing disease phenotypes and IgA production. Collectively, our findings provide insight into the significance of host glycosylation, more specifically GlcNAc-6-O sulfation on intestinal mucins, in protecting against obesity and intestinal inflammation via regulation of the gut microbiota.


Assuntos
Microbioma Gastrointestinal , Mucinas , Animais , Camundongos , Mucinas/metabolismo , Acetilglucosamina/metabolismo , Polissacarídeos/metabolismo , Inflamação , Obesidade
12.
Glia ; 59(6): 857-68, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21381115

RESUMO

The tumor suppressor adenomatous polyposis coli (APC) is a multifunctional protein that inhibits the Wnt/beta-catenin signaling pathway and regulates the microtubule and actin cytoskeletons. Using conditional knockout (CKO) mice in which the APC gene is inactivated in glial fibrillary acidic protein (GFAP)-expressing cells, we show a selective and critical role for APC in maintaining the morphology and function of cerebellar Bergmann glia, which are specialized astroglia that extend polarized radial processes from the Purkinje cell layer to the pial surface. APC-CKO mice developed Bergmann glia normally until the accumulation of beta-catenin started around postnatal day 10 (P10). Their radial fibers then became shortened with a marked reduction of branching collaterals and their cell bodies translocated into the molecular layer followed by loss of their pial contact and transformation into stellate-shaped cells by P21. Purkinje neurons were normal in appearance and number at P21, but there was significant loss of Purkinje neurons and cerebellar atrophy by middle age. Outside the cerebellum, neither beta-catenin accumulation nor morphological changes were identified in GFAP-expressing astroglia, indicating region-specific effects of APC deletion and an essential role for APC in maintaining the unique morphology of Bergmann glia as compared with other astroglia. These results demonstrate that loss of APC selectively disrupts the Bergmann glial scaffold in late postnatal development and leads to cerebellar degeneration with loss of Purkinje neurons in adults, providing another potential mechanism for region-specific non-cell autonomous neurodegeneration.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Doenças Cerebelares/genética , Cerebelo/crescimento & desenvolvimento , Predisposição Genética para Doença/genética , Degeneração Neural/genética , Neuroglia/metabolismo , Proteína da Polipose Adenomatosa do Colo/deficiência , Animais , Doenças Cerebelares/patologia , Doenças Cerebelares/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neuroglia/patologia , Células de Purkinje/patologia
13.
Stem Cells ; 28(11): 2053-2064, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21089118

RESUMO

The tumor suppressor adenomatous polyposis coli (APC) is a multifunctional protein that not only inhibits the Wnt signaling pathway by promoting the degradation of ß-catenin but also controls cell polarity, motility, and division. APC is abundantly expressed in the adult central nervous system, but its role in adult neurogenesis remains unknown. Using conditional deletion (or knockout) of APC (APC-CKO) from glial fibrillary acidic protein (GFAP)-expressing cells including adult neural stem cells (NSCs) in the subventricular zone and hippocampal dentate gyrus, we show that APC expression by these cells is a critical component of adult neurogenesis. Loss of APC function resulted in a marked reduction of GFAP-expressing NSC-derived new neurons, leading to the decreased volume of olfactory granule cell layer. Two distinct mechanisms account for impaired neurogenesis in APC-CKO mice. First, APC was highly expressed in migrating neuroblasts and APC deletion disturbed the differentiation from Mash1-expressing transient amplifying cells to neuroblasts with concomitant accumulation of ß-catenin. As a result, migrating neuroblasts decreased, whereas Mash1-expressing dividing cells reciprocally increased in the olfactory bulb of APC-CKO mice. Second, APC deletion promoted an exhaustion of the adult germinal zone. Functional NSCs and their progeny progressively depleted with age. These findings demonstrate that APC expression plays a key role in regulating intracellular ß-catenin level and neuronal differentiation of newly generated cells, as well as maintaining NSCs in the adult neurogenic niche. STEM CELLS 2010;28:2053-2064.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Diferenciação Celular/fisiologia , Ventrículos Cerebrais/citologia , Hipocampo/citologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Neurônios/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Diferenciação Celular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Reação em Cadeia da Polimerase
14.
Biomedicines ; 9(3)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801826

RESUMO

Junctional adhesion molecules (JAMs) are expressed in diverse types of stem and progenitor cells, but their physiological significance has yet to be established. Here, we report that JAMs exhibit a novel mode of interaction and biological activity in adipose-derived stromal/stem cells (ADSCs). Among the JAM family members, JAM-B and JAM-C were concentrated along the cell membranes of mouse ADSCs. JAM-C but not JAM-B was broadly distributed in the interstitial spaces of mouse adipose tissue. Interestingly, the JAM-C ectodomain was cleaved and secreted as a soluble form (sJAM-C) in vitro and in vivo, leading to deposition in the fat interstitial tissue. When ADSCs were grown in culture plates coated with sJAM-C, cell adhesion, cell proliferation and the expression of five mesenchymal stem cell markers, Cd44, Cd105, Cd140a, Cd166 and Sca-1, were significantly elevated. Moreover, immunoprecipitation assay showed that sJAM-C formed a complex with JAM-B. Using CRISPR/Cas9-based genome editing, we also demonstrated that sJAM-C was coupled with JAM-B to stimulate ADSC adhesion and maintenance. Together, these findings provide insight into the unique function of sJAM-C in ADSCs. We propose that JAMs contribute not only to cell-cell adhesion, but also to cell-matrix adhesion, by excising their ectodomain and functioning as a niche-like microenvironment for stem and progenitor cells.

15.
J Cell Biol ; 170(3): 413-27, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16061694

RESUMO

Maternal embryonic leucine zipper kinase (MELK) was previously identified in a screen for genes enriched in neural progenitors. Here, we demonstrate expression of MELK by progenitors in developing and adult brain and that MELK serves as a marker for self-renewing multipotent neural progenitors (MNPs) in cultures derived from the developing forebrain and in transgenic mice. Overexpression of MELK enhances (whereas knockdown diminishes) the ability to generate neurospheres from MNPs, indicating a function in self-renewal. MELK down-regulation disrupts the production of neurogenic MNP from glial fibrillary acidic protein (GFAP)-positive progenitors in vitro. MELK expression in MNP is cell cycle regulated and inhibition of MELK expression down-regulates the expression of B-myb, which is shown to also mediate MNP proliferation. These findings indicate that MELK is necessary for proliferation of embryonic and postnatal MNP and suggest that it regulates the transition from GFAP-expressing progenitors to rapid amplifying progenitors in the postnatal brain.


Assuntos
Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células-Tronco Multipotentes/fisiologia , Neurônios/fisiologia , Proteínas Serina-Treonina Quinases/biossíntese , Animais , Astrócitos/metabolismo , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Camundongos , Camundongos Transgênicos , Células-Tronco Multipotentes/metabolismo , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/biossíntese , Transativadores/metabolismo
16.
J Neurosci ; 28(28): 7231-43, 2008 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-18614693

RESUMO

Signaling mechanisms that regulate astrocyte reactivity and scar formation after spinal cord injury (SCI) are not well defined. We used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein (GFAP) promoter to conditionally delete the cytokine and growth factor signal transducer, signal transducer and activator of transcription 3 (STAT3), from astrocytes. After SCI in GFAP-Cre reporter mice, >99% of spinal cord cells that exhibited Cre activity as detected by reporter protein expression were GFAP-expressing astrocytes. Conditional deletion (or knock-out) of STAT3 (STAT3-CKO) from astrocytes in GFAP-Cre-loxP mice was confirmed in vivo and in vitro. In uninjured adult STAT3-CKO mice, astrocytes appeared morphologically similar to those in STAT3+/+ mice except for a partially reduced expression of GFAP. In STAT3+/+ mice, phosphorylated STAT3 (pSTAT3) was not detectable in astrocytes in uninjured spinal cord, and pSTAT3 was markedly upregulated after SCI in astrocytes and other cell types near the injury. Mice with STAT3-CKO from astrocytes exhibited attenuated upregulation of GFAP, failure of astrocyte hypertrophy, and pronounced disruption of astroglial scar formation after SCI. These changes were associated with increased spread of inflammation, increased lesion volume and partially attenuated motor recovery over the first 28 d after SCI. These findings indicate that STAT3 signaling is a critical regulator of certain aspects of reactive astrogliosis and provide additional evidence that scar-forming astrocytes restrict the spread of inflammatory cells after SCI.


Assuntos
Cicatriz/fisiopatologia , Gliose/fisiopatologia , Fator de Transcrição STAT3/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Análise de Variância , Animais , Animais Recém-Nascidos , Astrócitos/patologia , Astrócitos/fisiologia , Comportamento Animal , Contagem de Células/métodos , Células Cultivadas , Regulação da Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/biossíntese , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/deficiência , Traumatismos da Medula Espinal/patologia , Fatores de Tempo
17.
Eur J Neurosci ; 27(7): 1596-606, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18380662

RESUMO

Gliogenesis is an important component of cortical development during the postnatal period. Two macroglial cells are generated in a particular order, i.e. astrocytes first and oligodendrocytes later. The mechanisms underlying this sequence of glial differentiation are unknown but interactions with blood vessels are postulated to play a role. We show, using a mouse in-vitro coculture system, that endothelial cells promote astrocyte differentiation but inhibit oligodendrocyte differentiation of postnatal cortical progenitors. Endothelial cells produce bone morphogenetic proteins (BMPs) to activate Sma- and Mad-related protein (Smad) signalling in progenitors and the effects of endothelial cells on glial differentiation are blocked by the BMP antagonist Noggin. Differentiation of progenitors into astrocytes results in the inhibition of endothelial cell growth, accompanied by changes in gene expression of angiogenic factors, indicating bidirectional interactions between progenitors and endothelial cells. In vivo, Smad signalling is activated in various types of cortical cells including progenitors in association with astrogenesis but is inactivated before the peak of oligodendrogenesis. Capillary vessels isolated from the developing cortex express high levels of BMPs. Together, these results demonstrate that endothelial cells regulate glial differentiation by secreting BMPs in vitro and suggest a similar role in cortical gliogenesis in vivo.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Diferenciação Celular/fisiologia , Córtex Cerebral/citologia , Células Endoteliais/citologia , Neuroglia/citologia , Células-Tronco/citologia , Animais , Animais Recém-Nascidos , Bovinos , Células Cultivadas , Córtex Cerebral/crescimento & desenvolvimento , Técnicas de Cocultura/métodos , Células Endoteliais/fisiologia , Camundongos , Neuroglia/fisiologia , Células-Tronco/fisiologia
18.
Nat Neurosci ; 7(11): 1233-41, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15494728

RESUMO

Establishing the cellular identity in vivo of adult multipotent neural progenitors is fundamental to understanding their biology. We used two transgenic strategies to determine the relative contribution of glial fibrillary acidic protein (GFAP)-expressing progenitors to constitutive neurogenesis in the adult forebrain. Transgenically targeted ablation of dividing GFAP-expressing cells in the adult mouse subependymal and subgranular zones stopped the generation of immunohistochemically identified neuroblasts and new neurons in the olfactory bulb and the hippocampal dentate gyrus. Transgenically targeted cell fate mapping showed that essentially all neuroblasts and neurons newly generated in the adult mouse forebrain in vivo, and in adult multipotent neurospheres in vitro, derived from progenitors that expressed GFAP. Constitutively dividing GFAP-expressing progenitors showed predominantly bipolar or unipolar morphologies with significantly fewer processes than non-neurogenic multipolar astrocytes. These findings identify morphologically distinctive GFAP-expressing progenitor cells as the predominant sources of constitutive adult neurogenesis, and provide new methods for manipulating and investigating these cells.


Assuntos
Regulação da Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Neuroglia/fisiologia , Neurônios/fisiologia , Prosencéfalo/citologia , Células-Tronco/fisiologia , Análise de Variância , Animais , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Tamanho Celular , Proteínas do Domínio Duplacortina , Ganciclovir/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica/métodos , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neuropeptídeos/metabolismo , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Fosfopiruvato Hidratase/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/fisiologia , Ácidos Siálicos/metabolismo , Células-Tronco/efeitos dos fármacos , Timidina Quinase/genética , Tubulina (Proteína)/metabolismo , beta-Galactosidase/metabolismo
20.
Oncotarget ; 8(55): 93382-93391, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29212157

RESUMO

Schizophrenia is thought to be caused by a combination of genetic and environmental factors; however, its pathogenesis remains largely unknown. Here, we focus on the endothelial tight-junction protein claudin-5 (CLDN5), because the CLDN5 gene is mapped to the schizophrenia-associated 22q11.2 deletion region, and a single nucleotide polymorphism in the CLDN5 locus is also linked to schizophrenia. We show, by RT-qPCR and immunohistochemistry, that the expressions of CLDN5 mRNA and protein are significantly increased and decreased, respectively, in the schizophrenic prefrontal cortex (PFC) compared with control PFC. These changes were not observed in the schizophrenic visual cortex (VC), and neither the density nor diameter of the CD34-positive microvessels was altered in the schizophrenic PFC or VC. Interestingly, protein kinase A (PKA) was activated in the microvascular and perivascular regions of the schizophrenic PFC, and the pPKA-positive microvascular endothelial cells occasionally exhibited focal loss of CLND5. Since we previously demonstrated that cAMP induced CLDN5 mRNA expression and size-selective loosening of the endothelial barrier in PKA-independent and -dependent manners, respectively, a similar mechanism could contribute to the discrepancy between mRNA and protein expression of CLDN5 in the schizophrenic PFC. Taken collectively, these findings provide novel insights into the pathophysiology of schizophrenia.

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