Survey of Human Chromosome 21 Gene Expression Effects on Early Development in Danio rerio.
Survey of Human Chromosome 21 Gene Expression Effects on Early Development in Danio rerio.
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DOI：
10.1534/g3.118.200144
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发表时间：
2018-07-02
期刊：
影响因子：
--
通讯作者：
Reeves RH
中科院分区：
文献类型：
--
作者：
Edie S;Zaghloul NA;Leitch CC;Klinedinst DK;Lebron J;Thole JF;McCallion AS;Katsanis N;Reeves RH
人类21号染色体三体（Hsa 21）导致唐氏综合征（DS），这是与人类生存相容的最复杂的遗传条件之一。在早期胚胎发生过程中剂量驱动的单个Hsa 21基因过表达的生理后果的评估和由此产生的贡献，在哺乳动物中的DS病理是不听话的系统的方式。最近的一项研究着眼于Hsa 21基因的秀丽隐杆线虫直系同源物的一个子集的功能丧失，并确定了十个具有行为表型的候选者，但尚未进行等效的过表达实验。我们转向斑马鱼作为发育模型，并使用一些替代表型，我们筛选Hsa 21基因对早期胚胎发生的影响。我们制备了一个包含164个保守蛋白编码基因的cDNA文库，将mRNA注入早期胚胎，并在受精后5天（dpf）进行评估。24个基因产生了一个总的形态表型，其中11个可以可靠地复制。其中七个给出了与音刺猬（Shh）通路下调一致的表型;两个显示出指示缺陷神经嵴迁移的缺陷;一个始终导致心包水肿;一个是胚胎致死的。多个Hsa 21基因的组合注射揭示了加性和补偿效应，支持了复杂的遗传关系是产生DS的三体性末端表型的基础的观点。总之，我们的数据表明，该系统是有用的剂量敏感的基因对早期发育的影响的遗传解剖，并可以告知个人的基因座和它们的组合效应的贡献，DS的发病机制相关的表型。
Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS), one of the most genetically complex conditions compatible with human survival. Assessment of the physiological consequences of dosage-driven overexpression of individual Hsa21 genes during early embryogenesis and the resulting contributions to DS pathology in mammals are not tractable in a systematic way. A recent study looked at loss-of-function of a subset of Caenorhabditis elegans orthologs of Hsa21 genes and identified ten candidates with behavioral phenotypes, but the equivalent over-expression experiment has not been done. We turned to zebrafish as a developmental model and, using a number of surrogate phenotypes, we screened Hsa21 genes for effects on early embyrogenesis. We prepared a library of 164 cDNAs of conserved protein coding genes, injected mRNA into early embryos and evaluated up to 5 days post-fertilization (dpf). Twenty-four genes produced a gross morphological phenotype, 11 of which could be reproduced reliably. Seven of these gave a phenotype consistent with down regulation of the sonic hedgehog (Shh) pathway; two showed defects indicative of defective neural crest migration; one resulted consistently in pericardial edema; and one was embryonic lethal. Combinatorial injections of multiple Hsa21 genes revealed both additive and compensatory effects, supporting the notion that complex genetic relationships underlie end phenotypes of trisomy that produce DS. Together, our data suggest that this system is useful in the genetic dissection of dosage-sensitive gene effects on early development and can inform the contribution of both individual loci and their combinatorial effects to phenotypes relevant to the etiopathology of DS.
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影响因子：
2.1
作者：
Locke, Adam E.;Dooley, Kenneth J.;Tinker, Stuart W.;Cheong, Soo Yeon;Feingold, Eleanor;Allen, Emily G.;Freeman, Sallie B.;Torfs, Claudine P.;Cua, Clifford L.;Epstein, Michael P.;Wu, Michael C.;Lin, Xihong;Capone, George;Sherman, Stephanie L.;Bean, Lora J. H.
通讯作者：
Bean, Lora J. H.
DOI：
10.1161/circgenetics.111.960872
发表时间：
2012-06
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Li H;Cherry S;Klinedinst D;DeLeon V;Redig J;Reshey B;Chin MT;Sherman SL;Maslen CL;Reeves RH
通讯作者：
Reeves RH
影响因子：
4.5
作者：
Grossman TR;Gamliel A;Wessells RJ;Taghli-Lamallem O;Jepsen K;Ocorr K;Korenberg JR;Peterson KL;Rosenfeld MG;Bodmer R;Bier E
通讯作者：
Bier E
DOI：
10.1056/nejmoa1609009
发表时间：
2017-02-23
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lopez-Rivera E;Liu YP;Verbitsky M;Anderson BR;Capone VP;Otto EA;Yan Z;Mitrotti A;Martino J;Steers NJ;Fasel DA;Vukojevic K;Deng R;Racedo SE;Liu Q;Werth M;Westland R;Vivante A;Makar GS;Bodria M;Sampson MG;Gillies CE;Vega-Warner V;Maiorana M;Petrey DS;Honig B;Lozanovski VJ;Salomon R;Heidet L;Carpentier W;Gaillard D;Carrea A;Gesualdo L;Cusi D;Izzi C;Scolari F;van Wijk JA;Arapovic A;Saraga-Babic M;Saraga M;Kunac N;Samii A;McDonald-McGinn DM;Crowley TB;Zackai EH;Drozdz D;Miklaszewska M;Tkaczyk M;Sikora P;Szczepanska M;Mizerska-Wasiak M;Krzemien G;Szmigielska A;Zaniew M;Darlow JM;Puri P;Barton D;Casolari E;Furth SL;Warady BA;Gucev Z;Hakonarson H;Flogelova H;Tasic V;Latos-Bielenska A;Materna-Kiryluk A;Allegri L;Wong CS;Drummond IA;D'Agati V;Imamoto A;Barasch JM;Hildebrandt F;Kiryluk K;Lifton RP;Morrow BE;Jeanpierre C;Papaioannou VE;Ghiggeri GM;Gharavi AG;Katsanis N;Sanna-Cherchi S
通讯作者：
Sanna-Cherchi S
影响因子：
4.3
作者：
Das, Ishita;Reeves, Roger H.
通讯作者：
Reeves, Roger H.