RESUMO
The neural crest (NC) is a transient, multipotent and migratory cell population that generates an astonishingly diverse array of cell types during vertebrate development. These cells, which originate from the ectoderm in a region lateral to the neural plate in the neural fold, give rise to neurons, glia, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies (NCP) are a class of pathologies occurring in vertebrates, especially in humans that result from the abnormal specification, migration, differentiation or death of neural crest cells during embryonic development. Various pigment, skin, thyroid and hearing disorders, craniofacial and heart abnormalities, malfunctions of the digestive tract and tumors can also be considered as neurocristopathies. In this review we revisit the current classification and propose a new way to classify NCP based on the embryonic origin of the affected tissues, on recent findings regarding the molecular mechanisms that drive NC formation, and on the increased complexity of current molecular embryology techniques.
Assuntos
Desenvolvimento Embrionário/fisiologia , Crista Neural/embriologia , Crista Neural/fisiopatologia , Animais , Padronização Corporal/fisiologia , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Ectoderma , Transição Epitelial-Mesenquimal , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Melanócitos/citologia , Crista Neural/citologia , Sistema Nervoso Periférico/embriologia , Vertebrados/embriologiaRESUMO
During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.
Assuntos
Sistema Nervoso Central/embriologia , Sistema Nervoso Central/metabolismo , Netrina-1/metabolismo , Sistema Nervoso Periférico/embriologia , Sistema Nervoso Periférico/metabolismo , Animais , Movimento Celular/genética , Movimento Celular/fisiologia , Sistema Nervoso Central/citologia , Receptor DCC/deficiência , Receptor DCC/genética , Receptor DCC/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Netrina-1/deficiência , Netrina-1/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Sistema Nervoso Periférico/citologia , GravidezAssuntos
MicroRNAs/metabolismo , Atividade Motora/genética , Sistema Nervoso Periférico , Actinas/metabolismo , Fatores Etários , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Embrião não Mamífero , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , MicroRNAs/genética , Junção Neuromuscular/embriologia , Junção Neuromuscular/crescimento & desenvolvimento , Junção Neuromuscular/metabolismo , Sistema Nervoso Periférico/embriologia , Sistema Nervoso Periférico/crescimento & desenvolvimento , Sistema Nervoso Periférico/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
A transient and unique population of multipotent stem cells, known as neural crest cells (NCCs), generate a bewildering array of cell types during vertebrate development. An attractive model among developmental biologists, the study of NCC biology has provided a wealth of knowledge regarding the cellular and molecular mechanisms important for embryogenesis. Studies in numerous species have defined how distinct phases of NCC specification, proliferation, migration, and survival contribute to the formation of multiple functionally distinct organ systems. NCC contributions to the peripheral nervous system (PNS) are well known. Critical developmental processes have been defined that provide outstanding models for understanding how extracellular stimuli, cell-cell interactions, and transcriptional networks cooperate to direct cellular diversification and PNS morphogenesis. Dissecting the complex extracellular and intracellular mechanisms that mediate the formation of the PNS from NCCs may have important therapeutic implications for neurocristopathies, neuropathies, and certain forms of cancer.
Assuntos
Movimento Celular/fisiologia , Modelos Biológicos , Crista Neural/embriologia , Neurogênese/fisiologia , Sistema Nervoso Periférico/embriologia , Transdução de Sinais/fisiologia , Vertebrados/embriologia , Animais , Fatores de Crescimento Neural/fisiologiaRESUMO
Peripheral nerve sheath tumors are common neoplasms in daily practice. Diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer; but on occasion, they are diagnostically challenging (especially with locally aggressive and malignant tumors). This article aims to provide an update of the data (clinical, histological, immunohistochemistry and genomic) of benign, intermediate and malignant peripheral nerve sheath tumors, thanks to the latest WHO "Classification of Tumors of Soft Tissue and Bone", published in 2013, which includes a new chapter on "Nerve Sheath Tumors". Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches.
Assuntos
Neoplasias de Bainha Neural/patologia , Biomarcadores Tumorais , Tumor de Células Granulares/química , Tumor de Células Granulares/diagnóstico , Tumor de Células Granulares/patologia , Hamartoma/diagnóstico , Hamartoma/patologia , Humanos , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Neoplasias de Bainha Neural/química , Neoplasias de Bainha Neural/classificação , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/epidemiologia , Neoplasias de Bainha Neural/genética , Sistema Nervoso Periférico/embriologia , Prognóstico , Organização Mundial da SaúdeRESUMO
Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11 or ALL1 fused from chromosome 1q (MLLT11/AF1q) is a highly conserved 90 amino acid protein that functions in hematopoietic differentiation. Its translocation to the Trithorax locus has been implicated in malignancies of the hematopoietic system. However, the spatio-temporal profile of MLLT11 expression during embryonic development has not been characterized. Here we show that MLLT11 has a remarkably specific expression pattern in the developing central and peripheral nervous system. We find high levels of MLLT11 transcript and protein expression in the developing marginal zone of the cortex and spinal cord. MLLT11 co-localized with Tbr2 in the developing subplate region of the cortex and expanded to encompass the cortical plate at late fetal stages. Expression in the peripheral nervous system initiated at E9.5 in the facio-acoustic cranial ganglia and elaborated to identify all the cranio-facial and dorsal root ganglia by E10.5. We also observed expression in the eye and gastrointestinal tract, where MLLT11 transcripts localized to Tuj1-positive inner retinal layer and autonomic neurons, respectively. Altogether these results show that MLLT11 is a pan-neuronal marker, suggesting a role in neural differentiation in the central nervous system and neural crest-cell derived peripheral ganglia.
Assuntos
Córtex Cerebral/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Neurônios/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sistema Nervoso Autônomo/embriologia , Linhagem da Célula , Sistema Nervoso Central/embriologia , Gânglios Espinais/embriologia , Perfilação da Expressão Gênica , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Neurogênese , Sistema Nervoso Periférico/embriologia , Medula Espinal/embriologiaRESUMO
Cranial ectodermal placodes, a vertebrate innovation, contribute to the adenohypophysis and peripheral nervous system of the head, including the paired sense organs (eyes, nose, ears) and sensory ganglia of the Vth, VIIth, IXth and Xth cranial nerves. Fate-maps of groups of cells in amphibians, teleosts and amniotes have demonstrated that all placodes have a common origin in a horseshoe shaped territory, known as the preplacodal region (PPR), which surrounds the presumptive neural plate of the late gastrula/early neurula stage embryo. Given the extensive regional overlap of progenitors for different placodes in the chick embryo, it has been a matter of debate as to whether individual cells in the PPR are truly multipotent progenitors, with regard to placodal identity, or rather are lineage-biased or restricted to a specific placodal type prior to overt differentiation. Utilizing clonal analyses in vivo, we demonstrate here that the anterior PPR comprises some precursors that contribute either to the olfactory or lens placode well before they are spatially segregated or committed to either of these placodal fates. This suggests that lineage bias towards a specific placodal fate may coincide with induction of the PPR.
Assuntos
Evolução Clonal/fisiologia , Cristalino/embriologia , Mucosa Olfatória/embriologia , Sistema Nervoso Periférico/embriologia , Animais , Embrião de Galinha , Ectoderma/citologia , Ectoderma/embriologia , Gástrula/embriologia , Gástrula/inervação , Cabeça/embriologia , Crista Neural/citologia , Crista Neural/embriologia , Placa Neural/embriologia , Neurulação/fisiologia , Adeno-Hipófise/embriologia , Coloração e RotulagemRESUMO
The concept that target tissues determine the survival of neurons has inspired much of the thinking on neuronal development in vertebrates, not least because it is supported by decades of research on nerve growth factor (NGF) in the peripheral nervous system (PNS). Recent discoveries now help to understand why only some developing neurons selectively depend on NGF. They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS. Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.
Assuntos
Sistema Nervoso Central/metabolismo , Fator de Crescimento Neural/metabolismo , Neurogênese/fisiologia , Sistema Nervoso Periférico/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Apoptose , Sobrevivência Celular , Sistema Nervoso Central/embriologia , Humanos , Camundongos , Neurônios/metabolismo , Sistema Nervoso Periférico/embriologia , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Receptor trkC/metabolismoRESUMO
To analyze somatosensory neuron diversity in larval zebrafish, we identified several enhancers from the zebrafish and pufferfish genomes and used them to create five new reporter transgenes. Sequential deletions of three of these enhancers identified small sequence elements sufficient to drive expression in zebrafish trigeminal and Rohon-Beard (RB) neurons. One of these reporters, using the Fru.p2x3-2 enhancer, highlighted a somatosensory neuron subtype that expressed both the p2rx3a and pkcα genes. Comparison with a previously described trpA1b reporter revealed that it highlighted the same neurons as the Fru.p2x3-2 reporter. To determine whether neurons of this subtype possess characteristic peripheral branching morphologies or central axon projection patterns, we analyzed the morphology of single neurons. Surprisingly, although these analyses revealed diversity in peripheral axon branching and central axon projection, PKCα/p2rx3a/trpA1b-expressing RB cells did not possess obvious characteristic morphological features, suggesting that even within this molecularly defined subtype, individual neurons may possess distinct properties. The new transgenes created in this study will be powerful tools for further characterizing the molecular, morphological, and developmental diversity of larval somatosensory neurons.
Assuntos
Genes Reporter/genética , Larva/fisiologia , Células Receptoras Sensoriais/fisiologia , Transgenes/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Clonagem Molecular , Embrião não Mamífero , Proteínas de Fluorescência Verde/genética , Hibridização in Situ Fluorescente , Microscopia Confocal , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/embriologia , Proteína Quinase C-alfa/biossíntese , Proteína Quinase C-alfa/genética , Receptor trkA/genética , Células Receptoras Sensoriais/classificação , Especificidade da Espécie , Takifugu , Nervo Trigêmeo/embriologia , Nervo Trigêmeo/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
During vertebrate development, neural crest stem cells (NCSCs) give rise to neural cells of the peripheral nervous system and to a variety of mesenchymal cell types, including smooth muscle, craniofacial chondrocytes, and osteocytes. Consistently, mesenchymal stem cells (MSCs) have recently been shown to derive in part from the neural crest (NC), although the mechanisms underlying MSC generation remains to be identified. Here, we show that transforming growth factor ß (TGFß)-mediated suppression of the NCSC transcription factor Sox10 induces a switch in neural to mesenchymal potential in NCSCs. In vitro and in vivo, TGFß signal inactivation results in persistent Sox10 expression, decreased cell cycle exit, and perturbed generation of mesenchymal derivatives, which eventually leads to defective morphogenesis. In contrast, TGFß-mediated downregulation of Sox10 or its genetic inactivation suppresses neural potential, confers mesenchymal potential to NC cells in vitro, and promotes cell cycle exit and precocious mesenchymal differentiation in vivo. Thus, negative regulation of Sox10 by TGFß signaling promotes the generation of mesenchymal progenitors from NCSCs. Our study might lay the grounds for future applications demanding defined populations of MSCs for regenerative medicine.
Assuntos
Células-Tronco Mesenquimais/metabolismo , Crista Neural/metabolismo , Fatores de Transcrição SOXE/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Ciclo Celular , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese/genética , Crista Neural/citologia , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/embriologia , Sistema Nervoso Periférico/metabolismo , Reação em Cadeia da Polimerase , Fatores de Transcrição SOXE/antagonistas & inibidores , Transdução de Sinais , Fator de Crescimento Transformador beta/genéticaRESUMO
The cephalic neural crest (NC) cells delaminate from the neuroepithelium in large numbers and undergo collective cell migration under the influence of multiple factors including positive and negative taxis, cell-cell interactions mediating cell sorting, cell cooperation, and Contact-Inhibition of Locomotion. The migration has to be tightly regulated to allow NC cells to reach precise locations in order to contribute to various craniofacial structures such as the skeletal and peripheral nervous systems. Several birth defects, syndromes, and malformations are due to improper cephalic NC (CNC) migration, and NC cell migration bears important similarities to cancer cell invasion and metastasis dissemination. Therefore, understanding how CNC cells interpret multiple inputs to achieve directional collective cell migration will shed light on pathological situations where cell migration is involved.
Assuntos
Movimento Celular/fisiologia , Desenvolvimento Embrionário/fisiologia , Desenvolvimento Maxilofacial/fisiologia , Crista Neural/fisiologia , Crânio/embriologia , Animais , Osso e Ossos/embriologia , Comunicação Celular/fisiologia , Humanos , Metaloproteases/metabolismo , Sistema Nervoso Periférico/embriologia , Crânio/anatomia & histologiaRESUMO
Down-regulated in renal cell carcinoma 1 (DRR1) is mapped at 3p21.1, and is a candidate tumor suppressor gene. However, its biological roles have yet to be elucidated. Here, we developed polyclonal antibodies against DRR1 protein, and examined its expression during embryogenesis and carcinogenesis. The DRR1 protein was preferentially expressed in axonal projections of the central and peripheral nervous system of mice during embryonic days 10.5-16.5. Consistent with this expression pattern, the protein was detected in the neurites of primary cultured cortical neurons of rats at embryonic day 18.5. Survival of these cells was significantly inhibited by RNAi-induced downregulation of DRR1 expression. DRR1 was poorly expressed in established cancer cell lines, including neuroblastoma cells, whereas strong expression was observed in normal cells. A neuroblastoma model, MYCN transgenic mice, revealed that DRR1 protein was expressed in the celiac ganglion 2 weeks after birth when neuroblast hyperplasia was also observed; however, there was no longer any expression of DRR1 protein in tumors originating from the ganglion 8 weeks after birth. Together, our data indicate that DRR1 protein is expressed in normal cells, particularly in the nervous system during embryogenesis, is involved in neuronal cell survival, and is downregulated during neuroblastoma carcinogenesis.
Assuntos
Sistema Nervoso Central/embriologia , Neuroblastoma/patologia , Neurogênese , Proteínas Nucleares/metabolismo , Sistema Nervoso Periférico/embriologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Sistema Nervoso Central/metabolismo , Regulação para Baixo , Genes Supressores de Tumor , Humanos , Camundongos , Camundongos Transgênicos , Neuroblastoma/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Proteínas Nucleares/genética , Sistema Nervoso Periférico/metabolismo , Ratos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoAssuntos
Padronização Corporal/fisiologia , Melanócitos/fisiologia , Crista Neural/embriologia , Pele/embriologia , Células-Tronco/fisiologia , Animais , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Movimento Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Melanócitos/citologia , Modelos Animais , Crista Neural/citologia , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/embriologia , Pele/citologia , Células-Tronco/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Genome-wide screens were performed to identify transmembrane proteins that mediate axonal growth, guidance and target field innervation of somatosensory neurons. One gene, Linx (alias Islr2), encoding a leucine-rich repeat and immunoglobulin (LIG) family protein, is expressed in a subset of developing sensory and motor neurons. Domain and genomic structures of Linx and other LIG family members suggest that they are evolutionarily related to Trk receptor tyrosine kinases (RTKs). Several LIGs, including Linx, are expressed in subsets of somatosensory and motor neurons, and select members interact with TrkA and Ret RTKs. Moreover, axonal projection defects in mice harboring a null mutation in Linx resemble those in mice lacking Ngf, TrkA, and Ret. In addition, Linx modulates NGF-TrkA- and GDNF-GFRalpha1/Ret-mediated axonal extension in cultured sensory and motor neurons, respectively. These findings show that LIGs physically interact with RTKs and modulate their activities to control axonal extension, guidance and branching.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Gânglios Espinais/embriologia , Gânglios Espinais/crescimento & desenvolvimento , Gânglios Espinais/metabolismo , Camundongos , Camundongos Knockout , Neurônios Motores/fisiologia , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Sistema Nervoso Periférico/embriologia , Sistema Nervoso Periférico/crescimento & desenvolvimento , Sistema Nervoso Periférico/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Células Receptoras Sensoriais/fisiologia , Análise de Sequência de DNA , Homologia de Sequência , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/metabolismoAssuntos
Regeneração Nervosa/genética , Sistema Nervoso Periférico/lesões , Deformidades Congênitas das Extremidades Superiores/fisiopatologia , Neuropatias do Plexo Braquial/complicações , Neuropatias do Plexo Braquial/cirurgia , Humanos , Regeneração Nervosa/fisiologia , Sistema Nervoso Periférico/embriologia , Deformidades Congênitas das Extremidades Superiores/etiologiaRESUMO
The E2f3 locus encodes two Rb-binding gene products, E2F3a and E2F3b, which are differentially regulated during the cell cycle and are thought to be critical for cell cycle progression. We targeted the individual inactivation of E2f3a or E2f3b in mice and examined their contributions to cell proliferation and development. Chromatin immunoprecipitation and gene expression experiments using mouse embryo fibroblasts deficient in each isoform showed that E2F3a and E2F3b contribute to G(1)/S-specific gene expression and cell proliferation. Expression of E2f3a or E2f3b was sufficient to support E2F target gene expression and cell proliferation in the absence of other E2F activators, E2f1 and E2f2, suggesting that these isoforms have redundant functions. Consistent with this notion, E2f3a(-/-) and E2f3b(-/-) embryos developed normally, whereas embryos lacking both isoforms (E2f3(-/-)) died in utero. We also find that E2f3a and E2f3b have redundant and nonredundant roles in the context of Rb mutation. Analysis of double-knockout embryos suggests that the ectopic proliferation and apoptosis in Rb(-/-) embryos is mainly mediated by E2f3a in the placenta and nervous system and by both E2f3a and E2f3b in lens fiber cells. Together, we conclude that the contributions of E2F3a and E2F3b in cell proliferation and development are context dependent.
Assuntos
Proliferação de Células , Fator de Transcrição E2F3/genética , Fator de Transcrição E2F3/fisiologia , Desenvolvimento Embrionário , Genes do Retinoblastoma , Animais , Linhagem Celular , Sistema Nervoso Central/embriologia , Imunoprecipitação da Cromatina , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário/genética , Eritropoese/genética , Olho/embriologia , Feminino , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Sistema Nervoso Periférico/embriologia , Placenta/metabolismo , Placenta/patologia , Gravidez , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Ativação Transcricional , Trofoblastos/citologia , Trofoblastos/fisiologiaRESUMO
Cell proliferation and cell type specification are coordinately regulated during normal development. Cyclin E, a key G1/S cell cycle regulator, is regulated by multiple tissue-specific enhancers resulting in dynamic expression during Drosophila development. Here, we further characterized the enhancer that regulates cyclin E expression in the developing peripheral nervous system (PNS) and show that multiple sequence elements are required for the full cyclin E PNS enhancer activity. We further show that Wg signaling is important for the expression of cyclin E in the sensory organ precursor (SOP) cells through two conserved TCF binding sites. Blocking Wg signaling does not completely block SOP cell formation but does completely block SOP cell proliferation as well as the subsequent differentiation.
Assuntos
Ciclina E/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica no Desenvolvimento , Sistema Nervoso Periférico/embriologia , Transdução de Sinais , Proteína Wnt1/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Diferenciação Celular , Proliferação de Células , Sequência Conservada , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Células-Tronco Embrionárias/metabolismo , Elementos Facilitadores Genéticos/genética , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Dados de Sequência Molecular , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/metabolismo , Deleção de Sequência , Fatores de Transcrição TCF/metabolismoRESUMO
Drosophila PNS sense organs arise from single sensory organ precursor (SOP) cells through a series of asymmetric divisions. In a mis-expression screen for factors affecting PNS development, we identified string and dappled as being important for the proper formation of adult external sensory (ES) organs. string is a G2 regulator. dappled has no described function but is implicated in tumorigenesis. The mis-expression effect from string was analysed using timed over expression during adult ES-organ and, for comparison, embryonic Chordotonal (Ch) organ formation. Surprisingly, string mis-expression prior to SOP division gave the greatest effect in both systems. In adult ES-organs, this lead to cell fate transformations producing structural cells, whilst in the embryo organs were lost, hence differences within the lineages exist. Mis-expression of dappled, lead to loss and duplications of entire organs in both systems, potentially affecting SOP specification, in addition to affecting neuronal guidance.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Metaloproteínas/metabolismo , Organogênese , Sistema Nervoso Periférico/embriologia , Proteínas Tirosina Fosfatases/metabolismo , Órgãos dos Sentidos/embriologia , Animais , Proteínas de Transporte , Ciclo Celular/genética , Proteínas de Ciclo Celular , Proteínas de Drosophila/análise , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Feminino , Masculino , Metaloproteínas/genética , Mutação , Organogênese/genética , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/metabolismo , Proteínas Tirosina Fosfatases/análise , Proteínas Tirosina Fosfatases/genética , Órgãos dos Sentidos/citologia , Órgãos dos Sentidos/metabolismoRESUMO
Understanding the molecular mechanisms of stem cell maintenance is crucial for the ultimate goal of manipulating stem cells for the treatment of disease. Foxd3 is required early in mouse embryogenesis; Foxd3(-/-) embryos fail around the time of implantation, cells of the inner cell mass cannot be maintained in vitro, and blastocyst-derived stem cell lines cannot be established. Here, we report that Foxd3 is required for maintenance of the multipotent mammalian neural crest. Using tissue-specific deletion of Foxd3 in the neural crest, we show that Foxd3(flox/-); Wnt1-Cre mice die perinatally with a catastrophic loss of neural crest-derived structures. Cranial neural crest tissues are either missing or severely reduced in size, the peripheral nervous system consists of reduced dorsal root ganglia and cranial nerves, and the entire gastrointestinal tract is devoid of neural crest derivatives. These results demonstrate a global role for this transcriptional repressor in all aspects of neural crest maintenance along the anterior-posterior axis, and establish an unprecedented molecular link between multiple divergent progenitor lineages of the mammalian embryo.
Assuntos
Fatores de Transcrição Forkhead/fisiologia , Células-Tronco Multipotentes/citologia , Crista Neural/embriologia , Proteínas Repressoras/fisiologia , Animais , Padronização Corporal/fisiologia , Morte Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Fatores de Transcrição Forkhead/genética , Camundongos , Células-Tronco Multipotentes/fisiologia , Mutação , Crista Neural/anormalidades , Crista Neural/citologia , Sistema Nervoso Periférico/anormalidades , Sistema Nervoso Periférico/embriologia , Proteínas Repressoras/genética , Proteína Wnt1/genética , Proteína Wnt1/fisiologiaRESUMO
Neurofibromatosis is caused by the loss of neurofibromin (Nf1), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1-deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.