Pax6 limits the competence of developing cerebral cortical cells to respond to inductive intercellular signals.
Pax6 limits the competence of developing cerebral cortical cells to respond to inductive intercellular signals.
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DOI：
10.1371/journal.pbio.3001563
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发表时间：
2022-09
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
在多细胞生物中，稳定的特化细胞类型的发展依赖于控制诱导细胞间信号的机制和细胞对这些信号的响应能力。在发育中的大脑皮层中，祖细胞仅产生谷氨酸能兴奋性神经元，尽管暴露于有可能启动其他类型神经元产生的信号中，这表明它们的能力是有限的。在这里，我们验证了这种限制是由于转录因子Pax6的表达的假设。我们使用大量和单细胞RNAseq来证明，从皮层神经发生开始的条件皮质特异性Pax6缺失允许一些祖细胞产生类似于皮层外正常发现的异常谱系。对选择基因表达的分析表明，这些变化发生在特定的时空模式下。然后，我们比较了对照和pax6缺失皮质细胞对体内和体外细胞外信号操纵的反应。我们发现Pax6缺失增加了皮层祖细胞产生不适当谱系的能力，以响应正常存在于发育皮层中的细胞外因子，包括形态因子Shh和Bmp4。这些因子水平的区域差异可以解释体内Pax6缺失后命运变化的时空模式。我们认为，Pax6在皮质细胞发育中的主要作用是最大限度地降低它们的发育因同时参与其他基本功能的形成因子的潜在副作用而脱轨的风险。在多细胞生物中，稳定的特化细胞类型的发展依赖于控制诱导细胞间信号和细胞响应能力的机制。这项研究表明，皮质发育是由转录因子Pax6的保护作用稳定的，Pax6调节皮质细胞对局部环境中存在的潜在不稳定信号的反应能力。
The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence of cells to respond to such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being exposed to signals with the potential to initiate the production of other neuronal types, suggesting that their competence is limited. Here, we tested the hypothesis that this limitation is due to their expression of transcription factor Pax6. We used bulk and single-cell RNAseq to show that conditional cortex-specific Pax6 deletion from the onset of cortical neurogenesis allowed some progenitors to generate abnormal lineages resembling those normally found outside the cortex. Analysis of selected gene expression showed that the changes occurred in specific spatiotemporal patterns. We then compared the responses of control and Pax6-deleted cortical cells to in vivo and in vitro manipulations of extracellular signals. We found that Pax6 loss increased cortical progenitors’ competence to generate inappropriate lineages in response to extracellular factors normally present in developing cortex, including the morphogens Shh and Bmp4. Regional variation in the levels of these factors could explain spatiotemporal patterns of fate change following Pax6 deletion in vivo. We propose that Pax6’s main role in developing cortical cells is to minimize the risk of their development being derailed by the potential side effects of morphogens engaged contemporaneously in other essential functions. The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence of cells to respond. This study shows that cortical development is stabilized by the protective actions of the transcription factor Pax6, which adjusts the ability of cortical cells to respond to potentially destabilizing signals present in their local environment.
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影响因子：
11.8
作者：
Chau KF;Springel MW;Broadbelt KG;Park HY;Topal S;Lun MP;Mullan H;Maynard T;Steen H;LaMantia AS;Lehtinen MK
通讯作者：
Lehtinen MK
影响因子：
8.8
作者：
Caballero IM;Manuel MN;Molinek M;Quintana-Urzainqui I;Mi D;Shimogori T;Price DJ
通讯作者：
Price DJ
影响因子：
16.2
作者：
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通讯作者：
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影响因子：
16.2
作者：
Alcamo, Elizabeth A.;Chirivella, Laura;McConnell, Susan K.
通讯作者：
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影响因子：
5.3
作者：
Cheng, Xun;Hsu, Ching-mei;Monuki, Edwin S.
通讯作者：
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