Haploinsufficiency for the Six2 gene increases nephron progenitor proliferation promoting branching and nephron number.
Haploinsufficiency for the Six2 gene increases nephron progenitor proliferation promoting branching and nephron number.
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DOI：
10.1016/j.kint.2017.09.015
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发表时间：
2018-03
影响因子：
19.6
通讯作者：
Little MH
中科院分区：
文献类型：
--
作者：
Combes AN;Wilson S;Phipson B;Binnie BB;Ju A;Lawlor KT;Cebrian C;Walton SL;Smyth IM;Moritz KM;Kopan R;Oshlack A;Little MH
对肾脏中最终肾单位数量的调节知之甚少。然而，当自我更新的肾单位祖细胞群体致力于分化时，发生肾单位形成的停止。假设该祖细胞群体中的转录因子，如SIX 2，控制促进自我更新的基因的表达，使得纯合Six 2缺失导致过早定型和肾脏发育的早期停止。相反，假设Six 2杂合子不受影响。使用定量形态测定法，我们在这里证明了一个矛盾的18%增加输尿管分支和最终的肾单位数在Six 2杂合子，尽管Six 2蛋白和转录水平降低的证据。这伴随着肾单位祖细胞身份的明显转变，其中包括Cited 1和Meox 1的祖细胞基因的不同子集下调，而其他基因则不受影响。最终结果是肾单位祖细胞增殖增加，如通过升高的EDU标记、MYC蛋白增加和MYC靶基因的转录上调所评估的。通过将Six 2杂合性引入Fgf 20 −/−背景来减少增殖导致祖细胞群体的过早分化。总的来说，该数据证明了肾单位祖细胞对SIX 2蛋白水平的独特剂量反应，其中SIX 2在祖细胞增殖与自我更新中的作用是可分离的。
The regulation of final nephron number in the kidney is poorly understood. However, cessation of nephron formation occurs when the self-renewing nephron progenitor population commits to differentiation. Transcription factors within this progenitor population, such as SIX2, are assumed to control expression of genes promoting self-renewal such that homozygous Six2 deletion results in premature commitment and an early halt to kidney development. In contrast, Six2 heterozygotes were assumed to be unaffected. Using quantitative morphometry, we demonstrate here a paradoxical 18% increase in ureteric branching and final nephron number in Six2 heterozygotes, despite evidence for reduced levels of SIX2 protein and transcript. This is accompanied by a clear shift in nephron progenitor identity with a distinct subset of progenitor genes, including Cited1 and Meox1, downregulated, while others were unaffected. The net result was an increase in nephron progenitor proliferation, as assessed by elevated EDU labelling, an increase in MYC protein and transcriptional upregulation of MYC target genes. Reducing proliferation by introducing Six2 heterozygosity onto the Fgf20−/− background resulted in premature differentiation of the progenitor population. Overall, this data demonstrates a unique dose response of the nephron progenitors to the level of SIX2 protein in which the role of SIX2 in progenitor proliferation versus self-renewal is separable.
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影响因子：
64.5
作者：
Moreno, E;Basler, K
通讯作者：
Basler, K
影响因子：
64.8
作者：
Claveria, Cristina;Giovinazzo, Giovanna;Torres, Miguel
通讯作者：
Torres, Miguel
影响因子：
4.8
作者：
Huang, Le;Mokkapati, Sharada;Hu, Qianghua;Ruteshouser, E. Cristy;Hicks, M. John;Huff, Vicki
通讯作者：
Huff, Vicki
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG
影响因子：
13.6
作者：
Hoy, WE;Hughson, MD;Amann, K
通讯作者：
Amann, K