RESUMEN
Meningiomas are tumors arising from the meninges and represent the most frequent central nervous system tumors in adults. Recent large-scale genetic studies and preclinical meningioma mouse modelling led to a better comprehension of meningioma development and suggested evidences of close relationships between meningeal embryology and tumorigenesis. In this non-systematic review, we summarize the current knowledge on meningeal embryology and developmental biology, and illustrate how meningioma tumorigenesis is deeply related to meningeal embryology, concerning the potential cell of origin, the role of reactivation of embryonic stem cells, the influence of the embryonic tissue of origin, and the parallelism between topography-dependant molecular pathways involved in normal meninges and in meningioma development. Our study emphasizes why future studies on meningeal embryology are mandatory to affine our comprehension of mechanisms underlying meningioma initiation and development.
Asunto(s)
Carcinogénesis , Neoplasias Meníngeas/patología , Meninges/embriología , Meningioma/patología , Animales , Transformación Celular Neoplásica , Humanos , Neoplasias Meníngeas/etiología , Meningioma/etiologíaRESUMEN
The meninges are membranous layers surrounding the central nervous system. In the head, the meninges lie between the brain and the skull, and interact closely with both during development. The cranial meninges originate from a mesenchymal sheath on the surface of the developing brain, called primary meninx, and undergo differentiation into three layers with distinct histological characteristics: the dura mater, the arachnoid mater, and the pia mater. While genetic regulation of meningeal development is still poorly understood, mouse mutants and other models with meningeal defects have demonstrated the importance of the meninges to normal development of the calvaria and the brain. For the calvaria, the interactions with the meninges are necessary for the progression of calvarial osteogenesis during early development. In later stages, the meninges control the patterning of the skull and the fate of the sutures. For the brain, the meninges regulate diverse processes including cell survival, cell migration, generation of neurons from progenitors, and vascularization. Also, the meninges serve as a stem cell niche for the brain in the postnatal life. Given these important roles of the meninges, further investigation into the molecular mechanisms underlying meningeal development can provide novel insights into the coordinated development of the head.
Asunto(s)
Meninges/embriología , Meninges/metabolismo , Meninges/fisiología , Animales , Aracnoides/embriología , Aracnoides/metabolismo , Encéfalo/embriología , Encéfalo/metabolismo , Diferenciación Celular , Biología Evolutiva/métodos , Duramadre/embriología , Duramadre/metabolismo , Humanos , Piamadre/embriología , Piamadre/metabolismo , Cráneo/embriología , Cráneo/metabolismoRESUMEN
Cranial neural crest cells (CNCCs) give rise to cranial mesenchyme (CM) that differentiates into the forebrain meningeal progenitors in the basolateral and apical regions of the head. This occurs in close proximity to the other CNCC-CM-derivatives, such as calvarial bone and dermal progenitors. We found active Wnt signaling transduction in the forebrain meningeal progenitors in basolateral and apical populations and in the non-meningeal CM preceding meningeal differentiation. Here, we dissect the source of Wnt ligand secretion and requirement of Wnt/ß-catenin signaling for the lineage selection and early differentiation of the forebrain meninges. We find persistent canonical Wnt/ß-catenin signal transduction in the meningeal progenitors in the absence of Wnt ligand secretion in the CM or surface ectoderm, suggesting additional sources of Wnts. Conditional mutants for Wntless and ß-catenin in the CM showed that Wnt ligand secretion and Wnt/ß-catenin signaling were dispensable for specification and proliferation of early meningeal progenitors. In the absence of ß-catenin in the CM, we found diminished laminin matrix and meningeal hypoplasia, indicating a structural and trophic role of mesenchymal ß-catenin signaling. This study shows that ß-catenin signaling is required in the CM for maintenance and organization of the differentiated meningeal layers in the basolateral and apical populations of embryonic meninges.
Asunto(s)
Meninges/embriología , Mesodermo/metabolismo , Vía de Señalización Wnt , Animales , Linaje de la Célula , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Meninges/citología , Meninges/metabolismo , Mesodermo/citología , Mesodermo/embriología , Ratones , Prosencéfalo/citología , Prosencéfalo/embriología , Prosencéfalo/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: Traditionally, the central nervous system (CNS) has been viewed as an immune-privileged environment with no lymphatic vessels. This view was partially overturned by the discovery of lymphatic vessels in the dural membrane that surrounds the brain, in contact with the interior surface of the skull. We here examine the distribution and developmental timing of these lymphatic vessels. RESULTS: Using the Prox1-GFP BAC transgenic reporter and immunostaining with antibodies to lymphatic markers LYVE-1, Prox1, and Podoplanin, we have carried out whole-mount imaging of dural lymphatic vasculature at postnatal stages. We have found that between birth and postnatal day (P) 13, lymphatic vessels extend alongside dural blood vessels from the side of the skull toward the midline. Between P13 and P20, lymphatic vessels along the transverse sinuses reach the superior sagittal sinus (SSS) and extend along the SSS toward the olfactory bulb. CONCLUSIONS: Compared with the embryonic developmental timing of lymphatic vessels in other tissues, e.g. skin, dural lymphatic vessel development is dramatically delayed. This study provides useful anatomical data for continuing investigations of the fundamental mechanisms that underlie dural lymphatic vessel development. Developmental Dynamics 247:741-753, 2018. © 2018 Wiley Periodicals, Inc.
Asunto(s)
Vasos Linfáticos/embriología , Animales , Encéfalo/irrigación sanguínea , Meninges/embriología , Ratones , Ratones Transgénicos , Piel/embriologíaRESUMEN
Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder caused by a somatic activating mutation in GNAQ; it affects 1 in every 20,000 to 50,000 newborns. It is characterized by a facial Port-wine stain, leptomeningeal angiomatosis, and glaucoma. Seizures are the most common neurological manifestation and typically present in the first months of life. Glaucoma may be present at birth or develop later. Neuroimaging studies show leptomeningeal angiomatosis, supporting diagnosis. Standard treatment for Sturge-Weber syndrome includes laser treatment for the Port-wine stain, anticonvulsants, and medical or surgical treatment for the glaucoma. Prognosis depends on the extent of leptomeningeal involvement and the severity of the glaucoma.
Asunto(s)
Síndrome de Sturge-Weber , Anticonvulsivantes/uso terapéutico , Daño Encefálico Crónico/etiología , Daño Encefálico Crónico/prevención & control , Diagnóstico Precoz , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Glaucoma/tratamiento farmacológico , Glaucoma/etiología , Humanos , Láseres de Colorantes/uso terapéutico , Meninges/irrigación sanguínea , Meninges/embriología , Meninges/patología , Neuroimagen , Mancha Vino de Oporto/etiología , Mancha Vino de Oporto/cirugía , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Síndrome de Sturge-Weber/diagnóstico , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patología , Síndrome de Sturge-Weber/terapia , Venas/embriologíaRESUMEN
During embryonic development oligodendrocyte precursor cells (OPCs) are generated first in the ventral forebrain and migrate dorsally to occupy the cortex. The molecular cues that guide this migratory route are currently completely unknown. Here, we show that bone morphogenetic protein-4 (Bmp4), Bmp7, and Tgfß1 produced by the meninges and pericytes repelled ventral OPCs into the cortex at mouse embryonic stages. Ectopic activation of Bmp or Tgfß1 signaling before the entrance of OPCs into the cortex hindered OPC migration into the cortical areas. OPCs without Smad4 signaling molecules also failed to migrate into the cortex efficiently and formed heterotopia in ventral areas. OPC migration into the cortex was also dramatically reduced by conditional inhibition of Tgfß1 or Bmp expression from mesenchymal cells. The data suggest that mesenchymal Tgfß family proteins promote migration of ventral OPCs into the cortex during corticogenesis.
Asunto(s)
Proteína Morfogenética Ósea 4/metabolismo , Proteína Morfogenética Ósea 7/metabolismo , Movimiento Celular , Corteza Cerebral/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis , Oligodendroglía/metabolismo , Animales , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 7/genética , Corteza Cerebral/embriología , Meninges/embriología , Meninges/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Oligodendroglía/citología , Oligodendroglía/fisiología , Pericitos/metabolismo , Transducción de Señal , Proteína Smad4/genética , Proteína Smad4/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Nestin is a type VI intermediate filament protein known as a marker for progenitor cells that can be mostly found in tissues during the embryonic and fetal periods. In our study, we aimed to determine the expression of nestin in meninges covering the brain tissue at different developmental stages and in the new born. METHODS: In this study 10 human fetuses in different development stages between developmental weeks 9-34 and a newborn brain tissue were used. Fetuses in paraffin section were stained with H+E and nestin immunohistochemical staining protocol was performed. RESULTS: In this study, in the human meninges intense nestin expression was detected as early as in the 9th week of development. Intensity of this expression gradually decreased in later stages of development and nestin expression still persisted in a small population of newborn meningeal cells. CONCLUSION: In the present study, nestin positive cells gradually diminished in the developing and maturing meninges during the fetal period. This probably depends on initiation of a decrease in nestin expression and replacement with other tissue-specific intermediate filaments while the differentiation process continues. These differences can make significant contributions to the investigation and diagnosis of various pathological disorders (Tab. 1, Fig. 3, Ref. 36).
Asunto(s)
Meninges/embriología , Meninges/metabolismo , Nestina/metabolismo , Humanos , Inmunohistoquímica , Recién NacidoRESUMEN
Embryonic development is controlled by a small set of signal transduction pathways, with vastly different phenotypic outcomes depending on the time and place of their recruitment. How the same molecular machinery can elicit such specific and distinct responses, remains one of the outstanding questions in developmental biology. Part of the answer may lie in the high inherent genetic complexity of these signaling cascades, as observed for the Wnt-pathway. The mammalian genome encodes multiple Wnt proteins and receptors, each of which show dynamic and tightly controlled expression patterns in the embryo. Yet how these components interact in the context of the whole organism remains unknown. Here we report the generation of a novel, inducible transgenic mouse model that allows spatiotemporal control over the expression of Wnt5a, a protein implicated in many developmental processes and multiple Wnt-signaling responses. We show that ectopic Wnt5a expression from E10.5 onwards results in a variety of developmental defects, including loss of hair follicles and reduced bone formation in the skull. Moreover, we find that Wnt5a can have dual signaling activities during mouse embryonic development. Specifically, Wnt5a is capable of both inducing and repressing ß-catenin/TCF signaling in vivo, depending on the time and site of expression and the receptors expressed by receiving cells. These experiments show for the first time that a single mammalian Wnt protein can have multiple signaling activities in vivo, thereby furthering our understanding of how signaling specificity is achieved in a complex developmental context.
Asunto(s)
Desarrollo Embrionario/genética , Proteínas Represoras/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/genética , Animales , Huesos/anomalías , Huesos/efectos de los fármacos , Huesos/embriología , Calcificación Fisiológica/efectos de los fármacos , Calcificación Fisiológica/genética , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/efectos de los fármacos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Folículo Piloso/citología , Folículo Piloso/efectos de los fármacos , Folículo Piloso/embriología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Meninges/efectos de los fármacos , Meninges/embriología , Ratones , Ratones Transgénicos , Modelos Animales , Osteogénesis/efectos de los fármacos , Fenotipo , Embarazo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Piel/efectos de los fármacos , Piel/embriología , Piel/metabolismo , Tetraciclina/farmacología , Proteínas Wnt/genética , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt-5a , beta Catenina/metabolismoRESUMEN
Traditionally, the primary role of the meninges is thought to be structural, i.e., to act as a surrounding membrane that contains and cushions the brain with cerebrospinal fluid. During development, the meninges is formed by both mesenchymal and neural crest cells. There is now emerging evidence that subsets of undifferentiated stem cells might persist in the adult meninges. In this mini-review, we survey representative studies of brain-meningeal interactions and discuss the hypothesis that the meninges are not just protective membranes, but instead contain multiplex stem cell subsets that may contribute to central nervous system (CNS) homeostasis. Further investigations into meningeal multipotent cells may reveal a "hidden" target for promoting neurovascular remodeling and repair after CNS injury and disease.
Asunto(s)
Meninges/citología , Células Madre Multipotentes/fisiología , Adapaleno/análisis , Células Madre Adultas/fisiología , Animales , Isquemia Encefálica/fisiopatología , Sistema Nervioso Central/lesiones , Sistema Nervioso Central/fisiopatología , Enfermedades del Sistema Nervioso Central/terapia , Sistema Glinfático/citología , Homeostasis , Humanos , Masculino , Meninges/embriología , Cresta Neural/citología , Células-Madre Neurales/fisiología , Ratas , Ratas Sprague-Dawley , Regeneración/fisiologíaRESUMEN
Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10-10). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10-12). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10-2, Hazard Ratio 4.08, 95% Confidence Interval 1.28-13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.
Asunto(s)
ARN Polimerasas Dirigidas por ADN/genética , Neoplasias Meníngeas/genética , Meninges/embriología , Meninges/patología , Meningioma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/patología , Meningioma/diagnóstico , Meningioma/patología , Persona de Mediana Edad , Mutación/genética , Cresta Neural/embriología , Proteínas Proto-Oncogénicas c-akt/genética , Receptor Smoothened/genética , Adulto JovenRESUMEN
The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single-cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid, and pia. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial subpopulation marked by the expression of µ-crystallin. Developmental analysis reveals a progressive, ventral-to-dorsal maturation of telencephalic meninges. Our studies have generated an unparalleled view of meningeal fibroblasts, providing molecular profiles of embryonic meningeal fibroblasts by layer and yielding insights into the mechanisms of meninges development and function.
Asunto(s)
Encéfalo/metabolismo , Fibroblastos/metabolismo , Meninges/metabolismo , Transcriptoma , Animales , Encéfalo/citología , Encéfalo/embriología , Cristalinas/genética , Cristalinas/metabolismo , Humanos , Meninges/citología , Meninges/embriología , Ratones , Ratones Endogámicos C57BL , RNA-Seq , Análisis de la Célula IndividualRESUMEN
Using immunohistochemical methods, we have investigated the role of transforming growth factor-beta (TGF-beta) in the development of the mouse embryo. For detection of TGF-beta in 11-18-d-old embryos, we have used a polyclonal antibody specific for TGF-beta type 1 and the peroxidase-antiperoxidase technique. Staining of TGF-beta is closely associated with mesenchyme per se or with tissues derived from mesenchyme, such as connective tissue, cartilage, and bone. TGF-beta is conspicuous in tissues derived from neural crest mesenchyme, such as the palate, larynx, facial mesenchyme, nasal sinuses, meninges, and teeth. Staining of all of these tissues is greatest during periods of morphogenesis. In many instances, intense staining is seen in mesenchyme when critical interactions with adjacent epithelium occur, as in the development of hair follicles, teeth, and the submandibular gland. Marked staining is also seen when remodeling of mesenchyme or mesoderm occurs, as during formation of digits from limb buds, formation of the palate, and formation of the heart valves. The presence of TGF-beta is often coupled with pronounced angiogenic activity. The histochemical results are discussed in terms of the known biochemical actions of TGF-beta, especially its ability to control both synthesis and degradation of both structural and adhesion molecules of the extracellular matrix.
Asunto(s)
Ratones/embriología , Péptidos/fisiología , Animales , Huesos/embriología , Huesos/metabolismo , Tejido Conectivo/metabolismo , Fijadores , Corazón/embriología , Técnicas para Inmunoenzimas , Meninges/embriología , Meninges/metabolismo , Mesodermo/metabolismo , Miocardio/metabolismo , ARN Mensajero/metabolismo , Factores de Crecimiento TransformadoresRESUMEN
To identify regions involved in tissue specific regulation of transcription of the alpha1(VI) collagen chain, transgenic mice were generated carrying various portions of the gene's 5'-flanking sequence fused to the E. coli beta-galactosidase gene. Analysis of the transgene expression pattern by X-gal staining of embryos revealed that: (a) The proximal 0.6 kb of promoter sequence activated transcription in mesenchymal cells at sites of insertion of superficial muscular aponeurosis into the skin; tendons were also faintly positive. (b) The region between -4.0 and -5.4 kb from the transcription start site was required for activation of the transgene in nerves. It also drove expression in joints, in intervertebral disks, and in subepidermal and vibrissae mesenchyme. (c) The fragment comprised within -6.2 and -7.5 kb was necessary for high level transcription in skeletal muscle and meninges. Positive cells in muscle were mostly mononuclear and probably included connective tissue elements, although staining of myoblasts was not ruled out. This fragment also activated expression in joints, in intervertebral disks, and in subepidermal and vibrissae mesenchyme. (d) beta-Galactosidase staining in vibrissae induced by the sequences -4.0 to -5.4 and -6.2 to -7.5 was not coincident: with the latter sequence labeled nuclei were found mainly in the ventral and posterior quadrant, and, histologically, in the outer layers of mesenchyme surrounding and between the follicles, whereas with the former the remaining quadrants were positive and expressing cells were mostly in the inner layers of the dermal sheath. (e) Other tissues, notably lung, adrenal gland, digestive tract, which produce high amounts of collagen type VI, did not stain for beta-galactosidase. (f) Central nervous system and retina, in which the endogenous gene is inactive, expressed the lacZ transgene in most lines. The data suggest that transcription of alpha1(VI) in different tissues is regulated by distinct sequence elements in a modular arrangement, a mechanism which confers high flexibility in the temporal and spatial pattern of expression during development.
Asunto(s)
Colágeno/genética , Regiones Promotoras Genéticas/genética , Animales , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Prueba de Complementación Genética , Genoma , Disco Intervertebral/embriología , Disco Intervertebral/fisiología , Articulaciones/embriología , Articulaciones/fisiología , Masculino , Meninges/embriología , Meninges/fisiología , Mesodermo/fisiología , Ratones , Ratones Transgénicos , Músculo Esquelético/embriología , Músculo Esquelético/fisiología , Sistema Nervioso/embriología , Fenómenos Fisiológicos del Sistema Nervioso , Transcripción Genética/genética , Transgenes/genética , Vibrisas/embriología , Vibrisas/fisiologíaRESUMEN
The meninges are an important connective tissue envelope investing the brain. Their function is to provide a protective coating to the brain and also participate in the formation of blood-brain barrier. Understanding their anatomy is fundamental to understanding the location and spread of pathologies in relation to the layers. It also provides an insight into the characteristics of such pathologies when imaging them. This review aims to describe the anatomy of the meninges, and to demonstrate the imaging findings of specific features.
Asunto(s)
Meninges/anatomía & histología , Humanos , Imagen por Resonancia Magnética/métodos , Meninges/irrigación sanguínea , Meninges/embriología , Tomografía Computarizada por Rayos X/métodosRESUMEN
Loss of function of the mouse forkhead/winged helix transcription factor Foxc1 induces congenital hydrocephalus and impaired skull bone development due to failure of apical expansion of the bone. In this study we investigated meningeal development in the congenital hydrocephalus (ch) mouse with spontaneous loss of function mutant of Foxc1, around the period of initiation of skull bone apical expansion. In situ hybridization of Runx2 revealed active apical expansion of the frontal bone begins between embryonic day 13.5 and embryonic day 14.5 in the wild type, whereas expansion was inhibited in the mutant. Ultrastructural analysis revealed that three layers of the meninges begin to develop at E13.5 in the basolateral site of the head and subsequently progress to the apex in wild type. In ch homozygotes, although three layers were recognized at first at the basolateral site, cell morphology and structure of the layers became abnormal except for the pia mater, and arachnoidal and dural cells never differentiated in the apex. We identified meningeal markers for each layer and found that their expression was down-regulated in the mutant arachnoid and dura maters. These results suggest that there is a close association between meningeal development and the apical growth of the skull bones.
Asunto(s)
Factores de Transcripción Forkhead/genética , Regulación del Desarrollo de la Expresión Génica , Meninges/embriología , Cráneo/embriología , Animales , Aracnoides/embriología , Desarrollo Óseo/fisiología , Duramadre/embriología , Eliminación de Gen , Hidrocefalia/embriología , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Mutantes , Microscopía Electrónica de TransmisiónRESUMEN
Migration of neuronal precursor cells from the external germinal layer (EGL) to the internal granular layer (IGL) is a crucial process in the development of the mammalian cerebellar cortex. These cells make up the only precursor population known to migrate away from the surface of the brain. We studied the role of the chemokine stromal-derived factor 1 (SDF-1) in the cerebellar tissue of rats and knockout mice and found (i) that it functions as an attractive guidance cue for neuronal migration and (ii) that its secretion from non-neuronal meningeal tissue is important for controlling the migration of embryonic EGL cells.
Asunto(s)
Cerebelo/embriología , Cerebelo/metabolismo , Quimiocinas CXC/fisiología , Factores Quimiotácticos/fisiología , Meninges/metabolismo , Neuronas/metabolismo , Animales , Diferenciación Celular/fisiología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Cerebelo/citología , Quimiocina CXCL12 , Quimiocinas CXC/deficiencia , Quimiocinas CXC/farmacología , Factores Quimiotácticos/deficiencia , Factores Quimiotácticos/farmacología , Técnicas de Cocultivo , Inmunohistoquímica , Riñón/citología , Riñón/metabolismo , Meninges/citología , Meninges/embriología , Ratones , Ratones Noqueados , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Células Madre/citología , Células Madre/efectos de los fármacosRESUMEN
Nervous system development is a precisely orchestrated series of events requiring a multitude of intrinsic and extrinsic cues. Sortilin and SorCS2 are members of the Vps10p receptor family with complementary influence on some of these cues including the neurotrophins (NTs). However, the developmental time points where sortilin and SorCS2 exert their activities in conjunction or independently still remain unclear. In this study we present the characterization of the spatiotemporal expression pattern of sortilin and SorCS2 in the developing murine nervous system. Sortilin is highly expressed in the fetal nervous system with expression localized to distinct cell populations. Expression was high in neurons of the cortical plate and developing allocortex, as well as subpallial structures. Furthermore, the neuroepithelium lining the ventricles and the choroid plexus showed high expression of sortilin, together with the developing retina, spinal ganglia, and sympathetic ganglia. In contrast, SorCS2 was confined in a marked degree to the thalamus and, at E13.5, the floor plate from midbrain rostrally to spinal cord caudally. SorCS2 was also found in the ventricular zones of the ventral hippocampus and nucleus accumbens areas, in the meninges and in Schwann cells. Hence, sortilin and SorCS2 are extensively present in several distinct anatomical areas in the developing nervous system and are rarely co-expressed. Possible functions of sortilin and SorCS2 pertain to NT signaling, axon guidance and beyond. The present data will form the basis for hypotheses and study designs for unravelling the functions of sortilin and SorCS2 during the establishment of neuronal structures and connections.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Sistema Nervioso Central , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas del Tejido Nervioso/metabolismo , Nervios Periféricos , Receptores de Superficie Celular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Animales , Animales Recién Nacidos , Calbindina 2/metabolismo , Calbindinas/metabolismo , Sistema Nervioso Central/embriología , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/metabolismo , Plexo Coroideo/embriología , Plexo Coroideo/crecimiento & desarrollo , Plexo Coroideo/metabolismo , Embrión de Mamíferos , Epéndimo/embriología , Epéndimo/crecimiento & desarrollo , Epéndimo/metabolismo , Meninges/embriología , Meninges/crecimiento & desarrollo , Meninges/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Nervios Periféricos/embriología , Nervios Periféricos/crecimiento & desarrollo , Nervios Periféricos/metabolismo , Receptores de Superficie Celular/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
OBJECT: This study was undertaken to test a hypothesis that meningiomas of the midline skull base and spine are predominantly of the meningothelial histological subtype. METHODS: The cases of 794 consecutive patients who underwent resection for meningioma at the Cleveland Clinic between January 1991 and March 2004 were reviewed retrospectively. The authors analyzed the relationship between the tumors' histological subtypes and sites of origin in the 731 patients from this group who harbored tumors that were determined to be benign histologically (World Health Organization Grade I). Meningothelial meningiomas (MMs) accounted for 63.5% (464/731) of the Grade I tumors. The incidence of MM according to the site of origin was as follows: 84.9% (186/219) in the midline skull base, 58.3% (35/60) in the lateral skull base, 48.5% (183/377) in a non-skull base location, and 80% (60/75) in spinal locations. The incidence of MM in the midline skull base and spinal locations were significantly higher than in non-skull base or lateral skull base locations. CONCLUSIONS: Meningiomas of the midline neuraxis are predominantly meningotheliomas. Analysis of the increasingly available data on genetic and topographic characteristics of MMs suggests that they may represent a unique entity, contrary to the prevailing belief that all benign meningiomas are identical tumors.
Asunto(s)
Neoplasias Meníngeas/patología , Meningioma/patología , Neoplasias de la Base del Cráneo/patología , Neoplasias de la Médula Espinal/patología , Humanos , Neoplasias Meníngeas/etiología , Neoplasias Meníngeas/cirugía , Meninges/embriología , Meningioma/etiología , Meningioma/cirugía , Estudios Retrospectivos , Neoplasias de la Base del Cráneo/etiología , Neoplasias de la Base del Cráneo/cirugía , Neoplasias de la Médula Espinal/etiología , Neoplasias de la Médula Espinal/cirugíaRESUMEN
One general function for retinoic acid (RA) is pattern organization in the CNS. This regulatory factor has an essential role in spinal cord motor neuron and early posterior hindbrain development. In the anterior CNS, however, there is only a limited number of foci of RA synthesis, and less attention has been placed on regions such as the anterior hindbrain where RA synthesizing enzymes are absent. This study shows that a rich source of RA lies around the hindbrain from the RA synthetic enzyme retinaldehyde dehydrogenase-2 (RALDH2) present in the surrounding meninges and mesenchyme by embryonic day 13. RALDH2 is not distributed uniformly throughout the meninges but is restricted to territories over the developing hindbrain, suggesting that RA signaling may be localized to those regions. Further regulation of RA signaling is provided by the presence of a RA sink in the form of the CYP26B1 RA catabolic enzyme expressed in deeper regions of the brain. As a guide to the neural anatomy of hindbrain RA signaling, we used a mouse transgenic for a lacZ reporter gene driven by a RA response element (RAREhsplacZ) to identify regions of RA signaling. This reporter mouse provides evidence that RA signaling in the hindbrain after embryonic day 13 occurs in the regions of the cerebellum and precerebellar system adjacent to sources of RA, including the inferior olive and the pontine nuclei.
Asunto(s)
Meninges/embriología , Meninges/metabolismo , Rombencéfalo/embriología , Tretinoina/metabolismo , Aldehído Oxidorreductasas/genética , Aldehído Oxidorreductasas/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Cerebelo/embriología , Sistema Enzimático del Citocromo P-450/metabolismo , Genes Reporteros , Hibridación in Situ , Meninges/enzimología , Ratones , Ratones Transgénicos , Modelos Neurológicos , Neuronas/efectos de los fármacos , Neuronas/fisiología , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Receptores de Ácido Retinoico/biosíntesis , Receptores de Ácido Retinoico/genética , Elementos de Respuesta , Retinal-Deshidrogenasa , Ácido Retinoico 4-Hidroxilasa , Rombencéfalo/anatomía & histología , Rombencéfalo/metabolismo , Tretinoina/farmacología , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
LacZ reporter gene constructs were used to analyze the murine retinoic acid receptor beta (mRAR beta) gene promoter in transgenic mice. LacZ expression in transgenic mouse embryos with 250 bp of promoter sequences closely parallels that of RAR beta between embryonic days 8.5 and 12.5. This indicates that the -1 to -250 promoter region contains most regulatory elements required for tissue specific expression. Additional elements in the -250 to -625 region are required for high expression levels after day 12.5. Elements in the -625 to -3100 region are necessary to reproduce the RAR beta expression in the meninges and the eye mesenchyme. The expression pattern of the transgene and the endogenous RAR beta, as revealed by in situ hybridization, suggests an important role of the RAR beta in the developing nervous system.