Supplement to: Transcription control of retinal neuron specification and maturation
Supplement to: Transcription control of retinal neuron specification and maturation
批准号:
10429697
负责人:
Kevin Wright
金额:
$7.32万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-01 至 2024-12-31
关键词:
ATAC-seqAdoptedAffectAmacrine CellsAxonCellular MorphologyDefectDevelopmentDiseaseGenesGeneticGenomic approachIndividualInjuryInner Plexiform LayerMorphologyNervous system structureNeuronsPathway interactionsPatternPopulationPropertyRegulator GenesRetinaShapesSignal TransductionSpecific qualifier valueStereotypingStratificationTestingTranscriptional RegulationVisualexperimental studygain of functionhomeodomaininhibitory neuroninsightprogramspublic health relevanceregenerative therapyretinal neuronselective expressionstarburst amacrine celltranscription factortranscriptome sequencingvirtual
中文摘要
项目摘要/摘要
无长突细胞是视网膜内的主要抑制性神经元,形态上至少有45个。
不同的亚型,可通过其树枝的大小、形状和分层来区分
内部网状层(IPL)。大多数AC没有轴突,而是将信号整合到他们的
树枝状乔木。这种独特的布置意味着形式和功能在ACS中密切相关,
也许比任何其他类型的神经元都更有可能。然而,我们几乎不知道单个AC是如何
子类型是在开发过程中指定的,或者它们如何采用其刻板印象的形态。我们假设
选择性表达的转录因子(TF)可以很好地指导特定亚型的遗传程序
它们规定并指导了ACS的形态成熟。在AC人群中,同源结构域Tf
Isl1仅在星状突起的无长突细胞(SACs)中表达,而Gbx2仅在以前未鉴定的
中场非GABA、非甘氨酸能型急性冠脉综合征(Mf-nGnGs)。我们的初步结果显示
早期从AC前体中缺失Isl1或Gbx2会导致SAC和Mf-nGnG亚型缺陷
分别进行了详细说明。后来在迁移后的囊或Mf-nGnGs中删除Isl1或Gbx2会改变它们的
树枝状形态和层积模式。因此,Isl1和Gbx2似乎是初始
它们各自的AC亚型的规格和随后的形态成熟。我们将对此进行测试
具体目标如下:1)确定Isl1和Gbx2对于AC亚型是否必要和充分
规范和成熟。我们将使用条件损失函数和条件收益函数方法来确定
Isl1和Gbx2是否都是启动和维持末端分化的必要条件和充分条件
分别为SACS和MF-nGNG。此外,我们将使用基因组方法的组合(RNAseq,
ATACseq),以鉴定各自AC亚型中的Isl1和Gbx2基因调控网络。2)定义如何
Isl1和Gbx2调控SAC和Mf-nGnG的形态和功能连接。我们将首先确定如何
球囊中Isl1和Mf-nGnGs中Gbx2的丢失影响其定型树突的发育
形态和层积模式。然后我们将测试候选效应器基因和途径
参与树枝乔木的建立。最后,我们将确定Isl1和Gbx2的丢失
影响视觉回路中SACS和Mf-nGnGs的功能连接。总的来说,这些实验是
有望揭示选择性表达的转录因子如何指定AC亚型和驱动终端
赋予ACS独特形态特征的分化程序。我们预计这些
这些发现将揭示出广泛适用于发育中的神经系统的原理。
英文摘要
PROJECT SUMMARY/ABSTRACT
Amacrine cells (ACs) are the principle inhibitory neurons of the inner retina, with at least 45 morphologically
distinct subtypes that can be distinguished by the size, shape, and stratification of their dendritic arbors within
the inner plexiform layer (IPL). Most ACs do not have axons, and instead integrate signaling across their
dendritic arbors. This unique arrangement means that form and function are intimately related in ACs,
perhaps more so than in any other neuron type. However, we know virtually nothing about how individual AC
subtypes are specified during development, or how their adopt their stereotyped morphologies. We hypothesize
that selectively expressed transcription factors (TFs) are well poised to direct subtype-specific genetic programs
that specify and direct the morphological maturation of ACs. Within the AC population, the homeodomain TF
Isl1 is only expressed in starburst amacrine cells (SACs) and Gbx2 is only expressed in a previously unidentified
population of medium-field non-GABAeric, non-Glycinergic ACs (MF-nGnGs). Our preliminary results show
that early deletion of Isl1 or Gbx2 from AC precursors results in defects in SAC and MF-nGnG subtype
specification, respectively. Later deletion of Isl1 or Gbx2 in post-migratory SACs or MF-nGnGs alters their
dendritic morphology and stratification patterns. Therefore, Isl1 and Gbx2 appear to be required for the initial
specification and the subsequent morphological maturation of their respective AC subtypes. We will test this in
the following Specific Aims: 1) Determine whether Isl1 and Gbx2 are necessary and sufficient for AC subtype
specification and maturation. We will use conditional loss- and gain-of function approaches to determine
whether Isl1 and Gbx2 are both necessary and sufficient to initiate and maintain terminal differentiation in
SACs and MF-nGnGs, respectively. Furthermore, we will use a combination of genomic approaches (RNASeq,
ATACseq) to identify the Isl1 and Gbx2 gene regulator networks in the respective AC subtypes. 2) Define how
Isl1 and Gbx2 regulate SAC and MF-nGnG morphology and functional connectivity. We will first identify how
the loss of Isl1 in SACs and Gbx2 in MF-nGnGs affects the development of their stereotyped dendritic
morphology and stratification patterns. Then we will test candidate effector genes and pathways for their
involvement in the establishment of dendritic arbors. Finally, we will determine how the loss of Isl1 and Gbx2
affects the functional connectivity of SACs and MF-nGnGs in visual circuits. Together, these experiments are
expected to reveal how selectively expressed transcription factors specify AC subtypes and drive terminal
differentiation programs that endow ACs with their unique morphological properties. We expect that these
findings will reveal principles that are broadly applicable across the developing nervous system.
期刊论文(0)
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科研奖励(0)
会议论文
Transcriptional control of retinal neuron specification and maturation.
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批准号:10093946
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2021
-
负责人:Kevin Wright
-
依托单位:
Transcriptional control of retinal neuron specification and maturation.
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批准号:10600979
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2021
-
负责人:Kevin Wright
-
依托单位:
Transcriptional control of retinal neuron specification and maturation.
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批准号:10574464
-
项目类别:
-
资助金额:$7.32万
-
财政年份:2021
-
负责人:Kevin Wright
-
依托单位:
Transcriptional control of retinal neuron specification and maturation.
-
批准号:10318626
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项目类别:
-
资助金额:$37.35万
-
财政年份:2021
-
负责人:Kevin Wright
-
依托单位:
Transcriptional control of retinal neuron specification and maturation.
-
批准号:10846942
-
项目类别:
-
资助金额:$7.32万
-
财政年份:2021
-
负责人:Kevin Wright
-
依托单位:
The role of dystroglycan in neural circuit development.
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批准号:9308019
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项目类别:
-
资助金额:$33.69万
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财政年份:2016
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负责人:Kevin Wright
-
依托单位:
The role of dystroglycan in neural circuit development.
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批准号:9979988
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项目类别:
-
资助金额:$33.69万
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财政年份:2016
-
负责人:Kevin Wright
-
依托单位:
Evolution of Meiotic Mechanisms in Divergent Cytological Environments
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批准号:8457163
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项目类别:
-
资助金额:$5.22万
-
财政年份:2013
-
负责人:Kevin Wright
-
依托单位:
海外基金