Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization.
Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization.
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DOI：
10.1242/dev.02764
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发表时间：
2007-02
期刊：
影响因子：
--
通讯作者：
Price DJ
中科院分区：
文献类型：
--
作者：
Manuel M;Georgala PA;Carr CB;Chanas S;Kleinjan DA;Martynoga B;Mason JO;Molinek M;Pinson J;Pratt T;Quinn JC;Simpson TI;Tyas DA;van Heyningen V;West JD;Price DJ
转录因子Pax6的表达水平在皮质增殖区从吻侧高到尾侧中等的梯度中，在皮质新生过程中有所不同。以前的功能丧失研究表明，Pax6是正常的皮质前体细胞增殖、神经元分化、皮质分层和皮质区域化所必需的，但其表达水平是否以及如何影响其功能尚不清楚。我们研究了PAX77 YAC转基因小鼠的发育皮质，该转基因小鼠携带了几个拷贝的人PAX6基因及其完整的调控区。我们发现，PAX77胚胎以正常的空间模式表达Pax6，表达水平高达野生型的3倍。通过将PAX77小鼠与一种新的报告Pax6表达的YAC转基因株(DTy54)杂交，我们发现Pax6表达的增加受到负自我调节的限制。表达增加特异性地减少晚期皮质祖细胞的增殖，对PAX77↔野生型嵌合体的分析表明，该缺陷是细胞自主的。我们分析了PAX77小鼠的皮质区域化，发现虽然Pax6的丢失会使尾侧皮质区域向吻侧移动，但Pax6的过度表达在预测会使吻区向尾侧移动的水平上影响很小。这些发现表明，Pax6水平通过自身调节而稳定，皮质前体细胞的增殖对Pax6水平的变化敏感，而大脑皮层区域化则不敏感。
Levels of expression of the transcription factor Pax6 vary throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow gradient across the cortical proliferative zone. Previous loss-of-function studies have indicated that Pax6 is required for normal cortical progenitor proliferation, neuronal differentiation, cortical lamination and cortical arealization, but whether and how its level of expression affects its function is unclear. We studied the developing cortex of PAX77 YAC transgenic mice carrying several copies of the human PAX6 locus with its full complement of regulatory regions. We found that PAX77 embryos express Pax6 in a normal spatial pattern, with levels up to three times higher than wild type. By crossing PAX77 mice with a new YAC transgenic line that reports Pax6 expression (DTy54), we showed that increased expression is limited by negative autoregulation. Increased expression reduces proliferation of late cortical progenitors specifically, and analysis of PAX77↔wild-type chimeras indicates that the defect is cell autonomous. We analyzed cortical arealization in PAX77 mice and found that, whereas the loss of Pax6 shifts caudal cortical areas rostrally, Pax6 overexpression at levels predicted to shift rostral areas caudally has very little effect. These findings indicate that Pax6 levels are stabilized by autoregulation, that the proliferation of cortical progenitors is sensitive to altered Pax6 levels and that cortical arealization is not.
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影响因子：
64.8
作者：
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