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1.
Nature ; 617(7961): 599-607, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37138086

RESUMEN

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Vías Nerviosas , Humanos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Trombospondina 1/antagonistas & inhibidores , Gabapentina/farmacología , Gabapentina/uso terapéutico , Progresión de la Enfermedad , Cognición , Tasa de Supervivencia , Vigilia , Biopsia , Proliferación Celular/efectos de los fármacos
2.
Dev Dyn ; 244(3): 266-76, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25329498

RESUMEN

BACKGROUND: During development of the vertebrate eye, optic tissue is progressively compartmentalized into functionally distinct tissues. From the central to the peripheral optic cup, the original optic neuroepithelial tissue compartmentalizes, forming retina, ciliary body, and iris. The retina can be further sub-divided into peripheral and central compartments, where the central domain is specialized for higher visual acuity, having a higher ratio and density of cone photoreceptors in most species. RESULTS: Classically, models depict a segregation of the early optic cup into only two domains, neural and non-neural. Recent studies, however, uncovered discrete precursors for central and peripheral retina in the optic vesicle, indicating that the neural retina cannot be considered as a single unit with homogeneous specification and development. Instead, central and peripheral retina may be subject to distinct developmental pathways that underlie their specialization. CONCLUSIONS: This review focuses on lineage relationships in the retina and revisits the historical context for segregation of central and peripheral retina precursors before overt eye morphogenesis.


Asunto(s)
Organogénesis/fisiología , Retina/embriología , Células Madre/metabolismo , Animales , Humanos , Retina/citología , Células Madre/citología
3.
J Neurooncol ; 110(3): 305-13, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22983601

RESUMEN

Diffuse intrinsic pontine gliomas arise almost exclusively in children, and despite advances in treatment, the majority of patients die within 2 years after initial diagnosis. Because of their infiltrative nature and anatomic location in an eloquent area of the brain, most pontine gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and molecular biologic abnormalities associated with pontine gliomas, and is a substantial obstacle for the preclinical testing of targeted therapeutic agents for these tumors. We have established a human glioma cell line that originated from surgical biopsy performed on a patient with a pontine glioma. To insure sustainable in vitro propagation, tumor cells were modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase), and with a luciferase reporter to enable non-invasive bioluminescence imaging. The hTERT modified cells are tumorigenic in athymic rodents, and produce brainstem tumors that recapitulate the infiltrative growth of brainstem gliomas in patients.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias del Tronco Encefálico/patología , Glioma/patología , Puente , Animales , Biomarcadores de Tumor/metabolismo , Western Blotting , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/terapia , Niño , Femenino , Perfilación de la Expresión Génica , Glioma/genética , Glioma/terapia , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Ratas , Ratas Desnudas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
4.
Mol Vis ; 17: 3347-63, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22219630

RESUMEN

PURPOSE: The optic cup is created through invagination of the optic vesicle. The morphogenetic rearrangement creates a double-layered cup, with a hinge (the Optic Cup Lip) where the epithelium bends back upon itself. Shortly after the optic cup forms, it is thought to be sub-divided into separate lineages: i) pigmented epithelium in the outer layer; ii) presumptive iris and ciliary body at the most anterior aspect of the inner layer; and iii) presumptive neural retina in the remainder of the inner layer. We test the native developmental potential of the anterior cup to determine if it normally contributes to the retina. METHODS: Vital dye and green fluorescent protein (GFP) expressing replication-incompetent retroviral vectors were used to label cells in the nascent optic cup and follow their direct progeny throughout development. Label was applied to either the optic cup lip (n=40), or to the domain just posterior to the lip (n=20). Retroviral labeling is a permanent lineage marker and enabled the analysis of advanced stages of development. RESULTS: Labeling within the optic cup gave rise to labeled progeny in the posterior optic cup that differentiated as neural retina (20 of 20). In contrast, labeling cells in the optic cup lip gave rise to progeny of labeled cells arrayed in a linear progression, from the lip into the neural retina (36 of 40). Label was retained in cells at the optic cup lip, regardless of age at examination. In older embryos, labeled progeny delaminated from the optic cup lip to differentiate as muscle of the pupillary margin. CONCLUSIONS: The data show that the cells at the optic cup lip are a common progenitor population for pigmented epithelium, anterior eye tissues (ciliary body, iris, and pupillary muscle) and retinal neurons. The findings are supportive of an interpretation where the optic cup lip is a specialized niche containing a multipotent progenitor population.


Asunto(s)
Cuerpo Ciliar/citología , Iris/citología , Morfogénesis/fisiología , Células Madre Multipotentes/citología , Epitelio Pigmentado Ocular/citología , Retina/citología , Animales , Aves , Diferenciación Celular/fisiología , Embrión de Pollo , Cuerpo Ciliar/embriología , Colorantes Fluorescentes , Proteínas Fluorescentes Verdes/genética , Iris/embriología , Microinyecciones , Microscopía Fluorescente , Epitelio Pigmentado Ocular/embriología , Plásmidos , Retina/embriología , Retroviridae
5.
Mol Vis ; 16: 2701-17, 2010 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-21179237

RESUMEN

PURPOSE: Wnt2b is normally expressed at the optic cup lip and is implicated in ciliary body induction. The lens has often been considered an organizer for the anterior eye, but recent studies demonstrate that the anterior cell fates are correctly specified in the absence of the lens. This study uses Wnt2b as a marker to reveal the mechanism behind the specification of the anterior domain of the optic cup. METHODS: Developing chick embryos were used as a model system. Eyes were microsurgically manipulated to assess the role of the lens in the development of the anterior optic cup. Eyes were molecularly manipulated, using fibroblast growth factor expressing replication-incompetent retrovirus, introduced into the retinal pigmented epithelium (RPE) domain. Ectopic fibroblast growth factor transformed the RPE into nonpigmented epithelium (NPE; ciliary body). As the virus does not spread, discrete borders between RPE and NPE were experimentally created. Wnt2b expression was assessed after surgical and molecular manipulation. RESULTS: Contrary to expectations, we found that the lens is not able to induce Wnt2b expression in optic cup tissue: When the optic cup lip is experimentally misspecified such that it no longer contains the juxtaposition of pigmented and nonpigmented tissue, Wnt2b is not expressed. In addition, if the prelens ectoderm is removed from the optic vesicle before morphogenesis, the resulting lensless optic cup expresses Wnt2b even though it was not in contact with lens tissue. We also show that ectopic lenses do not induce Wnt2b in optic cup tissue. The ciliary body/anterior eye domain is specified at the border of RPE and the NPE of the ciliary body. During development, this border is normally found at the optic cup lip. We can manipulate tissue specification using retroviral-mediated gene transfer, and create ectopic borders between nonpigmented and pigmented tissue. At such borders, Wnt2b is ectopically expressed in the absence of lens contact. Finally, we describe a role for the lens in maintenance of Wnt2b expression and demonstrate support for this in two ways: First, we show that if the lens is removed from the formed optic cup, endogenous Wnt2b expression is specifically lost from the optic cup lip; and second, we show that while ectopic Wnt2b expression is initially found in the majority of ectopic borders, as eye development proceeds ectopic expression is maintained only in those borders that are close to the lens. CONCLUSIONS: Taken together, the results provide support for a model in which the anterior optic cup domain, as described in part by Wnt2b expression, is specified through the elaboration of a border within the optic neuroepithelium rather than through interactions with the surrounding environment.


Asunto(s)
Ojo/anatomía & histología , Ojo/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Proteínas Wnt/metabolismo , Animales , Biomarcadores/metabolismo , Embrión de Pollo , Colágeno Tipo IX/genética , Colágeno Tipo IX/metabolismo , Ojo/citología , Ojo/embriología , Factores de Crecimiento de Fibroblastos/farmacología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Cristalino/citología , Cristalino/efectos de los fármacos , Cristalino/embriología , Cristalino/metabolismo , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/embriología , Proteínas Wnt/genética
6.
Novartis Found Symp ; 250: 142-53; discussion 153-6, 276-9, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12956328

RESUMEN

Impulse-conducting Purkinje cells differentiate from myocytes during embryogenesis. In the embryonic chicken heart, this conversion of contractile myocytes into conduction cells occurs subendocardially and periarterially. The unique sites of Purkinje fibre differentiation suggest that a shear stress-induced paracrine signal from the endocardium and arterial beds may induce adjacent myocytes to differentiate into conduction cells. Consistent with this model, Purkinje fibre marker genes can be induced in cultured embryonic myocytes by endothelin (ET), an endothelial cell-derived signalling peptide. This inductive response is, however, gradually lost from myocytes as embryos develop, and mature myocytes express only genes characteristic of hypertrophy in response to ET. In vivo, active ET is produced, through proteolytic processing, from its precursor by ET-converting enzyme 1 (ECE1) and triggers signalling by binding to its receptors, ETA and ETB. In the embryonic heart, the expression of these ET signalling components changes dynamically, defining the site and timing of Purkinje fibre differentiation within the ventricular myocardium during chick embryogenesis.


Asunto(s)
Diferenciación Celular/fisiología , Inducción Embrionaria , Corazón/crecimiento & desarrollo , Ramos Subendocárdicos/embriología , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Enzimas Convertidoras de Endotelina , Endotelio/citología , Endotelio/metabolismo , Corazón/anatomía & histología , Corazón/fisiología , Metaloendopeptidasas , Morfogénesis , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Ramos Subendocárdicos/anatomía & histología , Ramos Subendocárdicos/fisiología , Receptores de Endotelina/metabolismo
7.
PLoS One ; 8(4): e61422, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23613848

RESUMEN

In the mature eye, three distinct tissue fates, retina, ciliary body, and iris, arrange with a strict linear organization along the central (back) to peripheral (front) axis. The establishment of this topographical relationship within the optic vesicle is not well understood. We use a targeted vital labeling strategy to test the derivation of mature eye tissues from the optic vesicle of the chick embryo. Fate mapping uncovers two distinct origins of the neural retina. Contrary to expectations, the central neural retina has a discrete origin within the posterior optic vesicle. The peripheral retina derives from the distal optic vesicle, sharing a common origin with more peripheral tissue fates. This study identifies for the first time two distinct retinal sub-domains, central and peripheral, which arise during embryogenesis. Identification of these discrete retinal compartments provides a framework for understanding functional and disease processes throughout retinal tissue.


Asunto(s)
Retina/embriología , Animales , Diferenciación Celular/fisiología , Embrión de Pollo , Cuerpo Ciliar/embriología , Ojo/embriología , Regulación del Desarrollo de la Expresión Génica , Iris/embriología
8.
Clin Exp Metastasis ; 29(4): 371-80, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22322278

RESUMEN

Medulloblastoma (MB) is the most common malignant primary brain tumor in children. Aggressive tumors that disseminate along the leptomeninges carry extremely poor prognoses. Mechanisms that predict dissemination are poorly understood. Our objective was to develop a reliable and reproducible model to study MB dissemination. We have created a chicken-human xenograft to study features of MB with leptomeningeal dissemination. Human MB cell lines (D283, Daoy), primary human MB cells (SF8113), and primary genetic mouse model (Math1cre:SmoM2 flox/flox) MB cells were either transfected to express green fluorescent protein (GFP) or were labeled with a membrane permeable green fluorescent probe. Cells were then injected as aggregates or implanted as pellets into the developing chicken brain immediately after neural tube closure at embryonic day 2 (E2). Most embryos were harvested three days after implantation (E5) though some were harvested up to E15. The developing brain was analyzed via whole mount fluorescent imaging and tissue section immunohistochemistry. Human and mouse MBs survived in the developing chicken central nervous system (CNS). They exhibited distinct patterns of incorporation and dissemination into the CNS that were consistent with observed phenotypes of the corresponding human patient or mouse host. Specifically, metastatic D283 cells disseminated along the leptomeninges whereas Daoy, primary mouse MB, and primary human MB cells did not. This work supports an avian-human xenograft as a successful model to study patterns of MB dissemination. Our model provides a basis for manipulating cell signaling mechanisms to understand critical targets involved in MB dissemination.


Asunto(s)
Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Neoplasias del Sistema Nervioso/patología , Animales , Embrión de Pollo , Preescolar , Humanos , Masculino , Ratones , Trasplante de Neoplasias , Células Tumorales Cultivadas
9.
Dev Dyn ; 237(11): 3260-9, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18942139

RESUMEN

We describe two replication incompetent retroviral vectors that co-express green fluorescent protein (GFP) and beta-galactosidase. These vectors incorporate either the avian reticuloendotheliosis (spleen necrosis virus; SNV) promoter or the chick beta-actin promoter, into the backbone of the murine leukemia (MLV) viral vector. The additional promoters drive transgene expression in avian tissue. The remainder of the vector is MLV-like, allowing high titer viral particle production by means of transient transfection. The SNV promoter produces high and early expression of introduced genes, enabling detection of the single copy integrated GFP gene in infected cells and their progeny in vivo. Substitution of the LacZ coding DNA with a relevant gene of interest will enable its co-expression with GFP, thus allowing visualization of the effect of specific and stable changes in gene expression throughout development. As the VSV-G pseudotyped viral vector is replication incompetent, changes in gene expression can be controlled temporally, by altering the timing of introduction.


Asunto(s)
Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Virus de la Leucemia Murina de Moloney/genética , Regiones Promotoras Genéticas/genética , Transgenes/genética , beta-Galactosidasa/genética , Actinas/genética , Animales , Embrión de Pollo , Expresión Génica , Proteínas Fluorescentes Verdes/biosíntesis , Ratones , Virus de la Necrosis Esplénica del Pato de Trager/genética , beta-Galactosidasa/biosíntesis
10.
Dev Biol ; 304(1): 272-85, 2007 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-17275804

RESUMEN

Upon morphogenesis, the simple neuroepithelium of the optic vesicle gives rise to four basic tissues in the vertebrate optic cup: pigmented epithelium, sensory neural retina, secretory ciliary body and muscular iris. Pigmented epithelium and neural retina are established through interactions with specific environments and signals: periocular mesenchyme/BMP specifies pigmented epithelium and surface ectoderm/FGF specifies neural retina. The anterior portions (iris and ciliary body) are specified through interactions with lens although the molecular mechanisms of induction have not been deciphered. As lens is a source of FGF, we examined whether this factor was involved in inducing ciliary body. We forced the pigmented epithelium of the embryonic chick eye to express FGF4. Infected cells and their immediate neighbors were transformed into neural retina. At a distance from the FGF signal, the tissue transitioned back into pigmented epithelium. Ciliary body tissue was found in the transitioning zone. The ectopic ciliary body was never in contact with the lens tissue. In order to assess the contribution of the lens on the specification of normal ciliary body, we created optic cups in which the lens had been removed while still pre-lens ectoderm. Ciliary body tissue was identified in the anterior portion of lens-less optic cups. We propose that the ciliary body may be specified at optic vesicle stages, at the same developmental stage when the neural retina and pigmented epithelium are specified and we present a model as to how this could be accomplished through overlapping BMP and FGF signals.


Asunto(s)
Cuerpo Ciliar/embriología , Inducción Embrionaria/fisiología , Factor 4 de Crecimiento de Fibroblastos/metabolismo , Modelos Biológicos , Animales , Embrión de Pollo , Inmunohistoquímica , Hibridación in Situ
11.
J Neurooncol ; 78(2): 113-21, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16554968

RESUMEN

Even though meningiomas are the second most common brain tumor in adults, little is known about the molecular basis of their growth and development. The lack of suitable cell culture model systems is an impediment to this understanding. Most studies on meningiomas rely on primary, early passage cell lines that eventually senesce or a few established cell lines that have been derived from aggressive variants of meningiomas. We have isolated three primary meningioma cell lines that are negative for telomerase activity. We can overcome the senescence of a Grade III derived meningioma cell line by expressing the telomerase catalytic subunit (hTERT), whereas Grade I meningioma cell lines require the expression of the human papillomavirus E6 and E7 oncogenes in conjunction with hTERT. Meningioma cell lines, immortalized in this manner, maintain their pre-transfection morphology and form colonies in vitro. We have confirmed the meningothelial origin of these cell lines by assessing expression of vimentin and desmoplakin, characteristic markers for meningiomas. Additionally, we have karyotyped these cell lines using array CGH and shown that they represent a spectrum of the genetic diversity seen in primary meningiomas. Thus, these cell lines represent novel cellular reagents for investigating the molecular oncogenesis of meningiomas.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral/metabolismo , Senescencia Celular/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias Meníngeas/genética , Meningioma/genética , Proteínas Oncogénicas Virales/metabolismo , Telomerasa/genética , Transformación Genética/genética , Técnicas de Cultivo de Célula/métodos , Senescencia Celular/fisiología , Proteínas de Unión al ADN/metabolismo , Desmoplaquinas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Transferencia de Gen , Humanos , Cariotipificación , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Papillomaviridae , Proteínas E7 de Papillomavirus/metabolismo , Telomerasa/metabolismo , Transfección/métodos , Vimentina/metabolismo
12.
Dev Neurosci ; 26(5-6): 456-65, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15855774

RESUMEN

The ciliary body is an essential tissue for the development and homeostasis of the vertebrate eye. Embryonically, the epithelial portion of the ciliary body derives from the neuroepithelium of the optic cup, however, it differentiates into a secretory tissue and produces an aqueous humor that sustains the lens and cornea, and maintains the requisite pressure within the orb. The unique differentiation of this portion of the optic cup is little understood. This article reviews what is known about the development of the ciliary body and presents some preliminary findings that may lead to a new model for the formation of the ciliary body.


Asunto(s)
Comunicación Celular/fisiología , Diferenciación Celular/fisiología , Cuerpo Ciliar/embriología , Inducción Embrionaria/fisiología , Células Epiteliales/metabolismo , Cristalino/embriología , Animales , Embrión de Pollo , Pollos , Cuerpo Ciliar/citología , Cuerpo Ciliar/metabolismo , Colágeno Tipo IX/metabolismo , Células Epiteliales/citología , Regulación del Desarrollo de la Expresión Génica/fisiología , Cristalino/citología , Cristalino/metabolismo , Retina/citología , Retina/embriología , Retina/metabolismo
13.
Dev Biol ; 259(2): 351-63, 2003 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-12871706

RESUMEN

The formation of the vertebrate optic cup is a morphogenetic event initiated after the optic vesicle contacts the overlying surface/pre-lens ectoderm. Placodes form in both the optic neuroepithelium and lens ectoderm. Subsequently, both placodes invaginate to form the definitive optic cup and lens, respectively. We examined the role of the lens tissue in inducing and/or maintaining optic cup invagination in ovo. Lens tissue was surgically removed at various stages of development, from pre-lens ectoderm stages to invaginating lens placode. Removal of the pre-lens ectoderm resulted in persistent optic vesicles that initiated neural retinal differentiation but failed to invaginate. In striking contrast, ablation of the lens placode gave rise to optic vesicles that underwent invagination and formed the optic cup. The results suggest that: (1) the optic vesicle neuroepithelium requires a temporally specific association with pre-lens ectoderm in order to undergo optic cup morphogenesis; and (2) the optic cup can form in the absence of lens formation. If ectopic BMP is added, a neural retina does not develop and optic cup morphogenesis fails, although lens formation appears normal. FGF-induced neural retina differentiation in the absence of the pre-lens ectoderm is not sufficient to create an optic cup. We hypothesize the presence of a signal coming from the pre-lens ectoderm that induces the optic vesicle to form an optic cup.


Asunto(s)
Ojo/embriología , Cristalino/embriología , Animales , Diferenciación Celular , Células Cultivadas , Embrión de Pollo , Ectodermo/metabolismo , Embrión no Mamífero , Cristalino/citología , Modelos Biológicos , Morfogénesis
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