Quantitative trait loci on chromosomes 9 and 19 modulate AII amacrine cell number in the mouse retina.
Quantitative trait loci on chromosomes 9 and 19 modulate AII amacrine cell number in the mouse retina.
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DOI：
10.3389/fnins.2023.1078168
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发表时间：
2023
影响因子：
4.3
通讯作者：
Keeley, Patrick W. W.
中科院分区：
文献类型：
--
作者：
Kulesh, Bridget;Bozadjian, Rachel;Parisi, Ryan J. J.;Leong, Stephanie A. A.;Kautzman, Amanda G. G.;Reese, Benjamin E. E.;Keeley, Patrick W. W.
调节基因功能或表达的序列变体影响各种可遗传的性状，包括群体中神经元的数量。本研究采用正向遗传学方法来确定候选致病基因及其序列变异控制的一种类型的视网膜神经元，AII无长突细胞的数量。来自26个重组近交系（RI）小鼠品系的数据来自亲本C57 BL/6 J（B6/J）和A/J实验室品系，用于鉴定调节细胞数量的基因组位点。RI菌株间的细胞数量存在较大差异，从低至1057，000个细胞到高至1087，000个细胞。数量性状基因座（QTL）分析显示三个前瞻性控制基因组位点，在染色体（Chrs）9，11和19，每个贡献加性效应，共同接近观察到的变异范围。复合区间作图验证了这些位点中的两个，和染色体置换株，其中A/J基因组的Chr 9或19的渗入B6/J遗传背景，表现出增加的AII无长突细胞的数量所预测的这两个QTL的影响。对各个基因组基因座的分析鉴定了候选控制基因，所述候选控制基因由其视网膜表达、其已建立的生物学功能以及预期调节基因功能或表达的序列变体的存在来限定。进一步详细研究了两个候选基因，Chr 19上的Dtx 4，作为Notch信号传导的调节因子，以及Chr 9上的Dixdc 1，WNT-β-连环蛋白信号传导途径的调节因子。出生后过表达的Dtx 4被发现减少无长突细胞的频率，而Dixdc 1基因敲除的视网膜含有过量的AII无长突细胞。每个基因中的序列变异被鉴定，是基因表达变异的可能来源，最终导致AII无长突细胞的最终数量。
Sequence variants modulating gene function or expression affect various heritable traits, including the number of neurons within a population. The present study employed a forward-genetic approach to identify candidate causal genes and their sequence variants controlling the number of one type of retinal neuron, the AII amacrine cell. Data from twenty-six recombinant inbred (RI) strains of mice derived from the parental C57BL/6J (B6/J) and A/J laboratory strains were used to identify genomic loci regulating cell number. Large variation in cell number is present across the RI strains, from a low of ∼57,000 cells to a high of ∼87,000 cells. Quantitative trait locus (QTL) analysis revealed three prospective controlling genomic loci, on Chromosomes (Chrs) 9, 11, and 19, each contributing additive effects that together approach the range of variation observed. Composite interval mapping validated two of these loci, and chromosome substitution strains, in which the A/J genome for Chr 9 or 19 was introgressed on a B6/J genetic background, showed increased numbers of AII amacrine cells as predicted by those two QTL effects. Analysis of the respective genomic loci identified candidate controlling genes defined by their retinal expression, their established biological functions, and by the presence of sequence variants expected to modulate gene function or expression. Two candidate genes, Dtx4 on Chr 19, being a regulator of Notch signaling, and Dixdc1 on Chr 9, a modulator of the WNT-β-catenin signaling pathway, were explored in further detail. Postnatal overexpression of Dtx4 was found to reduce the frequency of amacrine cells, while Dixdc1 knockout retinas contained an excess of AII amacrine cells. Sequence variants in each gene were identified, being the likely sources of variation in gene expression, ultimately contributing to the final number of AII amacrine cells.
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影响因子：
2.5
作者：
Nadeau, Joseph H.;Forejt, Jiri;Takada, Toyoyuki;Shiroishi, Toshihiko
通讯作者：
Shiroishi, Toshihiko
DOI：
10.1002/cne.22200
发表时间：
2009-12-10
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Voinescu PE;Kay JN;Sanes JR
通讯作者：
Sanes JR
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
影响因子：
6.8
作者：
Kivimäe S;Martin PM;Kapfhamer D;Ruan Y;Heberlein U;Rubenstein JL;Cheyette BN
通讯作者：
Cheyette BN
影响因子：
64.8
作者：
Kay, Jeremy N.;Chu, Monica W.;Sanes, Joshua R.
通讯作者：
Sanes, Joshua R.