Regulatory mechanisms of cerebellar lineage development
小脑谱系发育的调节机制
基本信息
- 批准号:10799998
- 负责人:
- 金额:$ 55.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAtaxiaBindingBinding SitesBrainCDK4 geneCell CycleCell Cycle ProgressionCell LineageCerebellar DiseasesCerebellumClustered Regularly Interspaced Short Palindromic RepeatsComplexCongenital cerebellar hypoplasiaDataDevelopmentDiseaseDown-RegulationEmbryoEnhancersEpigenetic ProcessFeedbackFoundationsGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHistone DeacetylaseHumanKnowledgeLearningModelingMotorNeuronsNucleic Acid Regulatory SequencesOutcomePlayPost-Translational RegulationPremature InfantProliferatingProteinsRepressionRisk FactorsRoleSignal TransductionSystemTestingTimeTranscription RepressorZinc Fingersautism spectrum disordercell typecognitive taskgenetic corepressorgranule cellinsulinoma associated 1medulloblastomamotor behaviornervous system disordernovelpostmitoticpostnatalprotein degradationsensory integrationtranscription factor
项目摘要
PROJECT SUMMARY
Granule cells (GCs) constitute over 95% of the cerebellar volume. They receive and integrate sensory, motor,
and non-sensorimotor signals to fine-tune motor behaviors and cognitive tasks. GCs are generated from
transiently proliferating granule cell precursors (GCPs) over a long time extending from early embryonic period
until first postnatal year in human. Accordingly, cerebellar hypoplasia is one of the most common brain
complications in premature infants with poor developmental outcomes. We have very limited basic knowledge
of how GC lineage is established. Our long term goals are to elucidate the regulatory mechanisms of GC lineage
development, and to understand how different risk factors cause cerebellar hypoplasia. A master regulator of
GCP development is the bHLH transcription factor Atoh1 that maintains the GCP fate through activation of its
own expression. This autoregulatory feedback loop is further supported by a cell cycle regulator Ccnd1 that
stabilizes Atoh1 protein from degradation. However, it remains unclear as to how Atoh1 and Ccnd1 expressions
are terminated to enable timely progression from GCPs to GCs. Our preliminary data suggest that Sin3A, a
component of histone deacetylase (Hdac)–containing transcriptional corepressor complex, is essential for GCP
differentiation by epigenetically silencing Atoh1 expression. We have also identified Insm1, a zinc-finger
transcription factor, as a potential partner of the Sin3A-Hdac complex that inhibits Atoh1 and Ccnd1 expression.
Based on these and other preliminary observations, we propose the novel hypothesis that Atoh1 expression is
dynamically controlled by H3K27 epigenetic signatures at the Atoh1 enhancer, with Insm1 as a key
transcriptional repressor disrupting the Atoh1 autoregulatory loop and cell cycle progression, and enabling GC
lineage differentiation. This hypothesis will be tested by determining (1) the epigenetic mechanism of Atoh1
expression and GC lineage differentiation, (2) Insm1 function and regulatory landscape during GC lineage
development, and (3) the contribution of Insm1 in Atoh1 protein stability and GC lineage progression.
项目总结
颗粒细胞占小脑体积的95%以上。它们接受并整合感觉、运动、
和非感觉运动信号来微调运动行为和认知任务。GCS由以下内容生成
胚胎早期长时间的瞬时增殖颗粒细胞前体(GCP)
直到人类出生后的第一年。因此,小脑发育不全是最常见的脑部疾病之一
发育不良早产儿的并发症。我们的基础知识非常有限
GC血统是如何建立的。我们的长期目标是阐明GC谱系的调节机制
了解不同的危险因素如何导致小脑发育不全。一位首席监管者
GCP的发育是bHLH转录因子Atoh1,它通过激活其
自己的表情。该自动调节反馈回路还由细胞周期调节器Ccnd1支持,该细胞周期调节器
稳定Atoh1蛋白的降解。然而,目前尚不清楚Atoh1和Ccnd1是如何表达的
被终止,以便能够及时从GCP升级到GCS。我们的初步数据表明,SIN3A,一个
组蛋白脱乙酰酶(HDAC)转录辅阻遏子复合体的组成部分,对GCP是必不可少的
通过表观遗传沉默Atoh1的表达进行分化。我们还鉴定了Insm1,一种锌手指
转录因子作为Sin3A-HDAC复合体的潜在合作伙伴,抑制Atoh1和Ccnd1的表达。
基于这些和其他初步观察,我们提出了新的假设,即Atoh1的表达是
由Atoh1增强子上的H3K27表观遗传签名动态控制,Insm1为关键
转录抑制物破坏Atoh1自动调节环和细胞周期进程,并使GC
世系分化。这一假说将通过确定(1)Atoh1的表观遗传机制来检验
表达与GC谱系分化,(2)Insm1在GC谱系中的功能和调控格局
(3)Insm1在Atoh1蛋白稳定性和GC谱系进展中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('CHIN CHIANG', 18)}}的其他基金
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
10001606 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
9356584 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
9235988 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling by Cellular Energetics
细胞能量学对 Shh 信号传导的调节
- 批准号:
9768250 - 财政年份:2016
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
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7267724 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7630604 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7145045 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7846200 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of Shh Signaling Activity in Limb Patterning
肢体模式中 Shh 信号活动的调节
- 批准号:
7439149 - 财政年份:2006
- 资助金额:
$ 55.48万 - 项目类别:
Control of Shh Activity and Signaling in the Neural Tube
神经管中 Shh 活动和信号传导的控制
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8323446 - 财政年份:2001
- 资助金额:
$ 55.48万 - 项目类别:
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