58 research outputs found
Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse
Understanding the molecular mechanisms that lead to birth defects is an important step towards improved primary prevention. Mouse embryos homozygous for the Kumba (Ku) mutant allele of Zic2 develop severe spina bifida with complete lack of dorsolateral hinge points (DLHPs) in the neuroepithelium. Bone morphogenetic protein (BMP) signalling is over-activated in Zic2Ku/Ku embryos, and the BMP inhibitor dorsomorphin partially rescues neural tube closure in cultured embryos. RhoA signalling is also over-activated, with accumulation of actomyosin in the Zic2Ku/Ku neuroepithelium, and the myosin inhibitor Blebbistatin partially normalises neural tube closure. However, dorsomorphin and Blebbistatin differ in their effects at tissue and cellular levels: DLHP formation is rescued by dorsomorphin but not Blebbistatin, whereas abnormal accumulation of actomyosin is rescued by Blebbistatin but not dorsomorphin. These findings suggest a dual mechanism of spina bifida origin in Zic2Ku/Ku embryos: BMP-dependent formation of DLHPs is faulty, together with RhoA-dependent F-actin accumulation in the neuroepithelium. Hence, we identify a multi-pathway origin of spina bifida in a mammalian system that may provide a developmental basis for understanding the corresponding multifactorial human defects
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Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2, a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX- 1-ko mice produced similar eicosanoid profiles in vitro: e.g. formation of TxA2, prostaglandin (PG) F2, 11-HETE and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less prothrombotic TxA2 and PGE2. Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen anti-thrombotic protection
Candidate Gene Screen in the Red Flour Beetle Tribolium Reveals Six3 as Ancient Regulator of Anterior Median Head and Central Complex Development
Several highly conserved genes play a role in anterior neural plate patterning of vertebrates and in head and brain patterning of insects. However, head involution in Drosophila has impeded a systematic identification of genes required for insect head formation. Therefore, we use the red flour beetle Tribolium castaneum in order to comprehensively test the function of orthologs of vertebrate neural plate patterning genes for a function in insect head development. RNAi analysis reveals that most of these genes are indeed required for insect head capsule patterning, and we also identified several genes that had not been implicated in this process before. Furthermore, we show that Tc-six3/optix acts upstream of Tc-wingless, Tc-orthodenticle1, and Tc-eyeless to control anterior median development. Finally, we demonstrate that Tc-six3/optix is the first gene known to be required for the embryonic formation of the central complex, a midline-spanning brain part connected to the neuroendocrine pars intercerebralis. These functions are very likely conserved among bilaterians since vertebrate six3 is required for neuroendocrine and median brain development with certain mutations leading to holoprosencephaly
Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma
Activating mutations in the gene encoding β-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a histologically benign but aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours. Recently, we generated an ACP mouse model and revealed that, as in human ACP, nucleocytoplasmic accumulation of β-catenin (β-catnc) and over-activation of the Wnt/β-catenin pathway occurs only in a very small proportion of cells, which form clusters. Here, combining mouse genetics, fluorescence labelling and flow-sorting techniques, we have isolated these cells from tumorigenic mouse pituitaries and shown that the β-catnc cells are enriched for colony-forming cells when cultured in stem cell-promoting media, and have longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells (PSCs). Global gene profiling analysis has revealed that these β-catnc cells express high levels of secreted mitogenic signals, such as members of the SHH, BMP and FGF family, in addition to several chemokines and their receptors, suggesting an important autocrine/paracrine role of these cells in the pathogenesis of ACP and a reciprocal communication with their environment. Finally, we highlight the clinical relevance of these findings by showing that these pathways are also up-regulated in the β-catnc cell clusters identified in human ACP. As well as providing further support to the concept that pituitary stem cells may play an important role in the oncogenesis of human ACP, our data reveal novel disease biomarkers and potential pharmacological targets for the treatment of these devastating childhood tumours.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0957-9) contains supplementary material, which is available to authorized users
THE I ANTIGEN AS AN IMMUNE COMPLEX RECEPTOR IN A CASE OF HAEMOLYTIC ANAEMIA INDUCED BY AN ANTIHISTAMINIC AGENT
Myelitis: Differences between multiple sclerosis and other aetiologies
Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs 41 ± 13; P = .02), more pronounced sphincter involvement (40.4% vs 27.3%; P = .05), greater multifocal involvement in spinal MRI (77.2% vs 26.5%; P = .001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P = .001), cervical location (82.5% vs 64.7%; P = .05) and posterior location (89.5% vs 41.2%; P = .001). Myelitis due to other aetiologies more frequently showed anterior location (47.1% vs 24.6%; P = .02), and central cord involvement (47.1% vs 14.1%; P = .001), with better recovery at one year of follow up (EDSS 2.0 vs 1.5; P = .01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS. Resumen: Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs 1,4; p = 0,001), localización cervical (82,5 vs 64,7%; p = 0,05) y localización posterior (89,5 vs 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs 24,6%; p = 0,02) y centromedular (47,1 vs 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico. Keywords: Myelitis, Multiple sclerosis, Idiopathic myelitis, Systemic diseases, Palabras clave: Mielitis, Esclerosis múltiple, Mielitis idiopáticas, Enfermedades sistémica
Mielitis. Diferencias entre esclerosis múltiple y otras etiologías
Resumen: Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs. 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs. 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs. 1,4; p = 0,001), localización cervical (82,5 vs. 64,7%; p = 0,05) y localización posterior (89,5 vs. 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs. 24,6%; p = 0,02) y centromedular (47,1 vs. 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs. 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico. Abstract: Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs. 41 ± 13; P = .02), more pronounced sphincter involvement (40.4 vs. 27.3%; P=.05), greater multifocal involvement in spinal MRI (77.2 vs. 26.5%; P=.001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P=.001), cervical location (82.5 vs. 64.7%; P=.05) and posterior location (89.5 vs. 41.2%; P=.001). Myelitis due to other aetiologies more frequently showed anterior location (47.1 vs. 24.6%; P=.02), and central cord involvement (47.1 vs. 14.1%; P=.001), with better recovery at one year of follow up (EDSS 2.0 vs. 1.5; P=.01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS. Palabras clave: Mielitis, Esclerosis múltiple, Mielitis idiopáticas, Enfermedades sistémicas, Keywords: Myelitis, Multiple sclerosis, Idiopathic myelitis, Systemic disease
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