Cell-autonomous repression of Shh by transcription factor Pax6 regulates diencephalic patterning by controlling the central diencephalic organizer.
Cell-autonomous repression of Shh by transcription factor Pax6 regulates diencephalic patterning by controlling the central diencephalic organizer.
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DOI：
10.1016/j.celrep.2014.07.051
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发表时间：
2014-09-11
期刊：
影响因子：
8.8
通讯作者：
Price DJ
中科院分区：
文献类型：
--
作者：
Caballero IM;Manuel MN;Molinek M;Quintana-Urzainqui I;Mi D;Shimogori T;Price DJ
在发育过程中，调控基因表达的区域特异性模式由信号中心控制，信号中心释放形态发生素，为周围细胞提供位置信息。因此，信号中心本身的调节至关重要。产生Shh的前脑组织者，丘脑内限制膜（ZLI）的大小和影响受到Pax 6的限制。通过对小鼠嵌合体的研究，我们发现Pax 6在ZLI周围的细胞中自主地起作用以阻断Shh的表达。免疫沉淀和荧光素酶分析表明Pax 6可以结合Shh启动子并抑制其功能。对嵌合体的分析表明，许多发生在Pax 6 −/−间脑细胞中的区域基因表达模式缺陷是由局部细胞间信号传导的非细胞自主位置依赖性缺陷引起的。阻断Pax 6 −/−突变体中的Shh信号转导可逆转主要间脑模式缺陷。我们的结论是，Pax 6的细胞自主压制Shh表达周围的ZLI是至关重要的正常间脑图案的许多方面。Pax 6限制了前脑组织者的作用，丘脑内的限制性内切酶Pax 6阻断间脑Shh表达细胞自主Pax 6的缺失导致非细胞自主间脑图案缺陷Pax 6 −/−突变体中Shh信号的阻断逆转了间脑图案缺陷大脑不同区域对特定特征的获取是由信号中心或组织者控制的，释放形态发生素向周围细胞提供信息。因此，信号中心本身的调节至关重要。Caballero等人他们发现，产生Shh的前脑组织者（丘脑内限制性神经元）的大小和影响受到Pax 6的限制，Pax 6会自动作用于细胞，阻止周围细胞中Shh的表达。Pax 6的缺失导致Shh表达的扩大，这反过来又导致区域错误指定。
During development, region-specific patterns of regulatory gene expression are controlled by signaling centers that release morphogens providing positional information to surrounding cells. Regulation of signaling centers themselves is therefore critical. The size and the influence of a Shh-producing forebrain organizer, the zona limitans intrathalamica (ZLI), are limited by Pax6. By studying mouse chimeras, we find that Pax6 acts cell autonomously to block Shh expression in cells around the ZLI. Immunoprecipitation and luciferase assays indicate that Pax6 can bind the Shh promoter and repress its function. An analysis of chimeras suggests that many of the regional gene expression pattern defects that occur in Pax6−/− diencephalic cells result from a non-cell-autonomous position-dependent defect of local intercellular signaling. Blocking Shh signaling in Pax6−/− mutants reverses major diencephalic patterning defects. We conclude that Pax6’s cell-autonomous repression of Shh expression around the ZLI is critical for many aspects of normal diencephalic patterning. Pax6 limits the effects of a forebrain organizer, the zona limitans intrathalamica Pax6 blocks diencephalic Shh expression cell autonomously Absence of Pax6 causes non-cell-autonomous diencephalic patterning defects Blocking Shh signaling in Pax6−/− mutants reverses diencephalic patterning defects The acquisition of specific features by different regions of the brain is controlled by signaling centers, or organizers, that release morphogens providing information to surrounding cells. The regulation of signaling centers themselves is therefore critical. Caballero et al. find that the size and the influence of a Shh-producing forebrain organizer, the zona limitans intrathalamica, are limited by Pax6, which acts cell autonomously to block Shh expression in surrounding cells. Loss of Pax6 causes expansion of Shh expression that, in turn, causes regional misspecification.
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影响因子：
4.6
作者：
Lek, Madelen;Dias, Jose M.;Ericson, Johan
通讯作者：
Ericson, Johan
影响因子：
16.2
作者：
Mi D;Carr CB;Georgala PA;Huang YT;Manuel MN;Jeanes E;Niisato E;Sansom SN;Livesey FJ;Theil T;Hasenpusch-Theil K;Simpson TI;Mason JO;Price DJ
通讯作者：
Price DJ
影响因子：
5.3
作者：
Hsu, SC;Galceran, J;Grosschedl, R
通讯作者：
Grosschedl, R
DOI：
10.1073/pnas.93.18.9346
发表时间：
1996-09-03
影响因子：
11.1
作者：
Marigo, V;Tabin, CJ
通讯作者：
Tabin, CJ
影响因子：
4.6
作者：
Jeong, Jae-Yeon;Einhorn, Zev;Guo, Su
通讯作者：
Guo, Su