Mesenchymal-neuroepithelial interactions in the developing telencephalon.
发育中的端脑间充质-神经上皮相互作用。
基本信息
- 批准号:9298711
- 负责人:
- 金额:$ 33.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:BrainBrain DiseasesCandidate Disease GeneCell CycleCellsCerebral cortexCerebrospinal FluidCharacteristicsChoroid Plexus EpitheliumCortical MalformationCoupledCytoskeletonDataDefectDevelopmentDiagnosticDiseaseDorsalDoseElectroporationEmbryoEmbryonic DevelopmentEtiologyEvolutionGenesGeneticGoalsGrowthHeadHoloprosencephalyHumanInjection of therapeutic agentLateralMammalsMediatingMegalencephalyMeningesMental disordersMesenchymalMesenchymeMicrogyriaMolecularMusNeocortexNeuroepithelialNeurogliaNeuronsPathway interactionsPatternPhenotypeProcessProductionProteinsPsyche structureRadialRoleSignal TransductionSignaling MoleculeSliceStructure of choroid plexusTelencephalonTestingTissuesWNT Signaling Pathwaybrain malformationexperimental studyimprovedin uteroinsightloss of functionmigrationmutantneocorticalneuroepitheliumneurogenesisnoveloverexpressionpreventprogenitorsegregationtranscription factortranscriptome sequencing
项目摘要
The cerebral cortex is the substrate of human mental prowess. It is believed that its increase in size, with
gyrification and expansion of upper layer neurons, mediates the growth of intellectual capacity during
mammalian evolution. Species-specific cortical cytoarchitecture is largely determined during embryogenesis,
integrating both cell autonomous and non-autonomous mechanisms. We are just beginning to understand the
mechanisms regulating cortical size and gyrification, with contribution of specific secreted molecules into
development of these cortical characteristics being particularly understudied. During development, the cerebral
cortex arises in the telencephalon, lateral to the telencephalic dorsal midline. Several signaling centers have
been described in the developing telencephalon, including a mesenchymal derivative meninges and the
telencephalic dorsal midline, subdivided into the choroid plexus (ChP) and cortical hem (CH). In addition to
secreting signaling molecules, the ChP also produces cerebrospinal fluid that nourishes and protects the brain,
while the CH is a major germinal zone in dorsal brain. While analyzing the role of the transcription factors
Lmx1a and Lmx1b, we found that Lmx1a/b double, but not single, mutants have an extraordinary phenotype of
a compromised telencephalic dorsal midline, and expanded, yet layered neocortex with local overgrowths
resembling gyri and an increased number of upper layer neurons. In addition, in Lmx1a/b double mutants, the
segregation of the dorsal midline lineage from more lateral neuroepithelium was severely compromised, with
dorsal midline progenitors aberrantly dispersing into more lateral neuroepithelium, including the neocortex. To
our surprise, we found that Lmx1a and 1b are never expressed in the neocortex nor coexpressed in the
telencephalon. Instead, during development, Lmx1a expression is limited to the ChP and CH while Lmx1b is
expressed in the adjacent head mesenchyme, suggesting that previously unrecognized mesenchymal-dorsal
midline interactions regulate key aspects of the telencephalic development. The goal of this proposal is to
define Lmx1a/b - dependent mesenchymal / neuroepithelial pathways regulating development of the
telencephalic dorsal midline and neocortex. In Aim 1 we will define how Lmx1a and 1b regulate the
telencephalic dorsal midline patterning and CH growth, two poorly understood processes, which are critical for
proper formation of the ChP and CH. In Aim 2 we will identify a new role of dorsal midline signaling in
neocortical gyrification and expansion of upper layer neurons, and define dorsal midline secreted molecules
mediating these processes. In Aim 3 we will define an Lmx1a/b-dependent molecular pathway regulating the
segregation of the dorsal midline lineage from more lateral neuroepithelium and show that this process is
critical to achieve proper cortical size in mice. Our studies will identify novel fundamental mechanisms
regulating telencephalic development and are likely to provide new insights into cortical evolution and human
developmental brain disorders.
大脑皮层是人类智力的基础。据信,其规模的增加,
神经元的旋转和扩张,介导了智力的增长,
哺乳动物进化种特异性皮层细胞结构在胚胎发生过程中很大程度上被确定,
集成了小区自治和非自治机制。我们才刚刚开始了解
调节皮质大小和脑回化的机制,以及特定分泌分子对脑回化的贡献。
这些皮质特征的发展尤其未被充分研究。在发育过程中,大脑
皮质位于端脑背侧中线的外侧。几个信号中心
在发育中的端脑中有描述,包括间充质衍生物脑膜和
端脑背中线,分为脉络丛(ChP)和皮质缘(CH)。除了
分泌信号分子,ChP还产生脑脊液,使大脑恢复和保护大脑,
而CH是背侧脑的主要生发区。在分析转录因子的作用时,
Lmx 1a和Lmx 1 B,我们发现Lmx 1 a/B双突变体,而不是单突变体,具有一种特殊的表型,
受损的端脑背中线,以及扩张但分层的新皮质,局部过度生长
类似于脑回,并且上层神经元的数量增加。此外,在Lmx 1 a/B双突变体中,
背中线谱系与更多外侧神经上皮的分离严重受损,
背中线祖细胞异常分散到更外侧的神经上皮,包括新皮质。到
令人惊讶的是,我们发现Lmx 1a和1b从未在新皮层中表达,也没有在大脑皮层中共同表达。
端脑相反,在发育过程中,Lmx 1a表达仅限于ChP和CH,而Lmx 1b表达仅限于ChP和CH。
在邻近的头部间充质中表达,这表明以前未被认识到的间充质背侧
中线相互作用调节端脑发育的关键方面。本提案的目的是
定义Lmx 1 a/B依赖性间充质/神经上皮途径,调节
端脑背中线和新皮质。在目标1中,我们将定义Lmx 1a和1b如何调节
端脑背中线图案化和CH生长,这两个知之甚少的过程,这是至关重要的
在目标2中,我们将确定背中线信号传导的新作用,
新皮层的回旋和上层神经元的扩张,并定义背中线分泌分子
调解这些过程。在目标3中,我们将定义一个Lmx 1a/b依赖的分子途径,
分离的背中线谱系从更多的侧面神经上皮,并表明这一进程是
这对在小鼠中获得适当的皮质大小至关重要。我们的研究将确定新的基本机制
调节端脑发育,并可能提供新的见解皮质进化和人类
大脑发育障碍
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Viktor Chizhikov其他文献
Viktor Chizhikov的其他文献
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{{ truncateString('Viktor Chizhikov', 18)}}的其他基金
Nf2-dependent regulation of neuronal scaling in the developing cerebellum
发育中小脑神经元缩放的 Nf2 依赖性调节
- 批准号:
10646360 - 财政年份:2022
- 资助金额:
$ 33.59万 - 项目类别:
Analysis of a novel duplication locus causing human cerebellar malformation
导致人类小脑畸形的新重复位点分析
- 批准号:
8740708 - 财政年份:2013
- 资助金额:
$ 33.59万 - 项目类别:
Analysis of a novel duplication locus causing human cerebellar malformation
导致人类小脑畸形的新重复位点分析
- 批准号:
8383400 - 财政年份:2012
- 资助金额:
$ 33.59万 - 项目类别:
Analysis of a novel duplication locus causing human cerebellar malformation
导致人类小脑畸形的新重复位点分析
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8463050 - 财政年份:2012
- 资助金额:
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7849022 - 财政年份:2009
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$ 33.59万 - 项目类别:
Tippy a novel mouse model for human ataxia epilepsy
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