NUCLEAR DYNAMICS IN RETINAL DEVELOPMENT AND HOMEOSTASIS
视网膜发育和稳态中的核动力学
基本信息
- 批准号:8617278
- 负责人:
- 金额:$ 37.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAgingAnimal ModelApicalAtrophicBrainCell CycleCell NucleusCellsCentral Nervous System DiseasesComplexConeCytoskeletonDefectDevelopmentDiseaseEtiologyFailureFamilyGenesGeneticHomeostasisHumanImpairmentKnowledgeLamin Type BLinkMammalsMicrophthalmosMitoticModelingMolecularMolecular AnalysisMolecular MotorsMovementMusMutationNatureNeuroepithelial CellsNeuronsNewborn InfantNuclearNuclear EnvelopeNuclear TranslocationOptic NervePathologyPatternPhasePhenotypePhotoreceptorsPhysiologicalPopulationPositioning AttributeProtein IsoformsProteinsRetinaRetinalRetinal ConeRetinal DiseasesRetinal DysplasiaRoleSideSystemTestingTimeTissuesTranscriptional RegulationTransgenic ModelTransgenic Organismsbasedystroglycanopathyin vivomacromolecular assemblymaculamigrationmouse modelnerve stem cellnervous system disorderneuroepitheliumneurogenesisneurogeneticsnovelpostnatalpreventprogenitorpublic health relevanceretinal neuronretinal progenitor cellretinogenesisstem
项目摘要
DESCRIPTION (provided by applicant): Nuclear movements within neuronal progenitors and post-mitotic neurons underlie fundamental aspects of CNS development. Accordingly, failure of these nuclear movements are associated to severe neurodevelopmental defects such as abnormal cortical lamination, optic nerve hypoplasia and atrophy, retinal dysplasia, macular hypoplasia and microphthalmia. Our limited understanding of the physiological relevance of these nuclear movements stems, in part, from the current lack of appropriate animal models to interfere with nucleokinesis. We recently validated a novel transgenic strategy that interferes with nuclear movements within specific cells and/or tissues in vivo. This strategy is based on the inducible disruption of "Linkers of the Nucleoskeleton to the Cytoskeleton" (LINC complexes), a family of macromolecular assemblies that span the nuclear envelope and provide anchor points for molecular motors and cytoskeletal networks to the nucleus. Using this transgenic strategy, we will examine the role of LINC complexes in interkinetic nuclear migration that consists of oscillations of retinal progenitor nuclei in phase with the cell cycle. Because nuclear translocation is strictly required for the migration of cortical post-mitotic neurons, we will examine whether LINC complex disruption affects the migration of newborn retinal neurons towards their final laminar position. The phenotypical consequences resulting from induced alterations of nuclear movements during retinogenesis will be fully examined in adult retinas, a set of results that may provide new models of congenital retinal disorders. We recently observed that cone nuclei positioning are severely altered upon LINC complex disruption, a phenotype that is strikingly similar to the progressive mispositioning of cone nuclei within the aging human retina. Here, the morphological and physiological consequences of cone nuclei mispositioning will be carefully analyzed in our mouse model. Cone nuclei mispositioning phenotype in adult retina originates from the inability of cone precursor nuclei to migrate apically during postnatal retinal development. Because B-type lamins directly interact with nucleoplasmic interfaces of LINC complexes, their involvement in cone nuclei positioning will be examined. Cytoplasmic interfaces of LINC complex are represented by Nesprins, a group of structurally- related proteins encoded by four distinct genes whose transcriptional regulation leads to the synthesis of multiple isoforms. Currently, the identity of Nesprin isoform(s) expressed in the CNS remains unknown, a knowledge gap that prevents the examination of the molecular nature of LINC complex interactions with molecular motors. Here, we will identify Nesprin isoforms expressed in retinal neurons and their progenitors. Because mutations of Nesprin genes are genetically linked to an increasing number of neurological disorders, our results may further emphasize CNS-specific isoforms of Nesprins whose mutations underlie human neurological disorders.
描述(由申请人提供):神经元祖细胞和有丝分裂后神经元内的核运动是CNS发育的基础。因此,这些核运动的失败与严重的神经发育缺陷相关,例如异常皮质分层、视神经发育不全和萎缩、视网膜发育不良、黄斑发育不全和小眼症。我们对这些核运动的生理相关性的理解有限,部分原因是目前缺乏适当的动物模型来干扰核分裂。我们最近验证了一种新的转基因策略,干扰特定细胞和/或组织内的核运动在体内。该策略基于“核骨架与细胞骨架的连接体”(LINC复合物)的诱导性破坏,LINC复合物是跨越核膜并为分子马达和细胞骨架网络提供到核的锚点的大分子组装体家族。使用这种转基因策略,我们将研究LINC复合物的作用,在interkinetic核迁移,包括振荡的视网膜祖细胞核的阶段与细胞周期。由于核转位是严格要求的皮质有丝分裂后神经元的迁移,我们将研究是否LINC复杂的破坏影响新生视网膜神经元向其最终层的位置迁移。在视网膜发生过程中诱导的核运动改变所导致的表型后果将在成人视网膜中进行全面检查,这一组结果可能提供先天性视网膜疾病的新模型。我们最近观察到,锥核定位严重改变后LINC复合物破坏,表型,这是惊人的相似的锥核在老化的人视网膜内进行性错位。在这里,锥核错位的形态和生理后果将在我们的小鼠模型中仔细分析。成年视网膜中的视锥细胞核错位表型起源于视锥细胞前体细胞核在出生后视网膜发育过程中不能向顶部迁移。由于B型核纤层蛋白直接与LINC复合物的核质界面相互作用,因此将检查它们参与视锥细胞核定位。LINC复合体的细胞质界面由Nesprins代表,Nesprins是一组结构相关的蛋白质,由四种不同的基因编码,其转录调节导致多种同种型的合成。目前,在CNS中表达的Nesprin同种型的身份仍然未知,这是一个知识空白,阻止了对LINC复合物与分子马达相互作用的分子性质的检查。在这里,我们将确定在视网膜神经元和它们的祖细胞中表达的Nesprin亚型。由于Nesprin基因突变与越来越多的神经系统疾病有遗传联系,我们的研究结果可能进一步强调CNS特异性Nesprin亚型,其突变是人类神经系统疾病的基础。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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DIDIER HODZIC其他文献
DIDIER HODZIC的其他文献
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{{ truncateString('DIDIER HODZIC', 18)}}的其他基金
NUCLEAR DYNAMICS IN RETINAL DEVELOPMENT AND HOMEOSTASIS
视网膜发育和稳态中的核动力学
- 批准号:
8502978 - 财政年份:2013
- 资助金额:
$ 37.24万 - 项目类别:
NUCLEAR DYNAMICS IN RETINAL DEVELOPMENT AND HOMEOSTASIS
视网膜发育和稳态中的核动力学
- 批准号:
9037670 - 财政年份:2013
- 资助金额:
$ 37.24万 - 项目类别:
The nucleus-cytoskeleton connection in health and disease
健康和疾病中的核-细胞骨架联系
- 批准号:
8134011 - 财政年份:2008
- 资助金额:
$ 37.24万 - 项目类别:
The nucleus-cytoskeleton connection in health and disease
健康和疾病中的核-细胞骨架联系
- 批准号:
7694287 - 财政年份:2008
- 资助金额:
$ 37.24万 - 项目类别:
The nucleus-cytoskeleton connection in health and disease
健康和疾病中的核-细胞骨架联系
- 批准号:
7583474 - 财政年份:2008
- 资助金额:
$ 37.24万 - 项目类别:
The nucleus-cytoskeleton connection in health and disease
健康和疾病中的核-细胞骨架联系
- 批准号:
7914158 - 财政年份:2008
- 资助金额:
$ 37.24万 - 项目类别:
The nucleus-cytoskeleton connection in health and disease
健康和疾病中的核-细胞骨架联系
- 批准号:
7918616 - 财政年份:2008
- 资助金额:
$ 37.24万 - 项目类别:
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