Pax6 is required intrinsically by thalamic progenitors for the normal molecular patterning of thalamic neurons but not the growth and guidance of their axons.
Pax6 is required intrinsically by thalamic progenitors for the normal molecular patterning of thalamic neurons but not the growth and guidance of their axons.
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DOI：
10.1186/s13064-015-0053-7
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发表时间：
2015-10-31
影响因子：
3.6
通讯作者：
Price DJ
中科院分区：
文献类型：
--
作者：
Clegg JM;Li Z;Molinek M;Caballero IM;Manuel MN;Price DJ
在小鼠胚胎中，Pax 6转录因子在丘脑神经元的祖细胞中表达，但不在丘脑神经元本身中表达。它的零突变导致丘脑祖细胞的早期错误模式。众所周知，由Pax 6 −/−祖细胞产生的丘脑神经元不会与皮质形成正常的连接，但原因尚不清楚。我们调查了丘脑固有缺陷的程度。我们首先证实，在组成型Pax 6 −/−突变体中，丘脑神经元的轴突无法进入端脑，相反，它们中的许多人采取异常路径到达下丘脑，其Slits的表达通常会排斥它们。我们发现，丘脑神经元在Pax 6 −/−突变体中表现出Slit受体Robo 2的表达减少，这可能会增强其轴突进入下丘脑的能力。然而，值得注意的是，在由Pax 6 −/−和Pax 6 +/+细胞混合组成的嵌合体中，Pax 6 −/−丘脑神经元能够产生轴突，这些轴突离开间脑，以正常的轨迹穿过端脑，避开下丘脑。尽管它们的分子模式异常（它们表达Nkx2.2，不像正常的丘脑神经元）和Robo 2的表达减少，这种情况还是发生了。在条件突变体中，当丘脑轴突开始生长时，前脑中Pax 6的急性缺失并不能阻止丘脑皮质束的发育，这表明早期的丘脑外模式和/或形态缺陷是Pax 6 −/−组成型突变体中丘脑皮质束失败的主要原因。我们的研究结果表明，Pax 6是所需的丘脑祖细胞的正常分子模式的丘脑神经元，他们产生，但丘脑神经元不需要正常的Pax 6依赖的图案，成为有能力生长轴突，可以适当地引导。
In mouse embryos, the Pax6 transcription factor is expressed in the progenitors of thalamic neurons but not in thalamic neurons themselves. Its null-mutation causes early mis-patterning of thalamic progenitors. It is known that thalamic neurons generated by Pax6−/− progenitors do not develop their normal connections with the cortex, but it is not clear why. We investigated the extent to which defects intrinsic to the thalamus are responsible. We first confirmed that, in constitutive Pax6−/− mutants, the axons of thalamic neurons fail to enter the telencephalon and, instead, many of them take an abnormal path to the hypothalamus, whose expression of Slits would normally repel them. We found that thalamic neurons show reduced expression of the Slit receptor Robo2 in Pax6−/− mutants, which might enhance the ability of their axons to enter the hypothalamus. Remarkably, however, in chimeras comprising a mixture of Pax6−/− and Pax6+/+ cells, Pax6−/− thalamic neurons are able to generate axons that exit the diencephalon, take normal trajectories through the telencephalon and avoid the hypothalamus. This occurs despite abnormalities in their molecular patterning (they express Nkx2.2, unlike normal thalamic neurons) and their reduced expression of Robo2. In conditional mutants, acute deletion of Pax6 from the forebrain at the time when thalamic axons are starting to grow does not prevent the development of the thalamocortical tract, suggesting that earlier extra-thalamic patterning and /or morphological defects are the main cause of thalamocortical tract failure in Pax6−/− constitutive mutants. Our results indicate that Pax6 is required by thalamic progenitors for the normal molecular patterning of the thalamic neurons that they generate but thalamic neurons do not need normal Pax6-dependent patterning to become competent to grow axons that can be guided appropriately.