Chapman Heather, Riesenberg Amy, Ehrman Lisa A, Kohli Vikram, Nardini Diana, Nakafuku Masato, Campbell Kenneth, Waclaw Ronald R
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Dev Biol. 2018 Oct 1;442(1):115-126. doi: 10.1016/j.ydbio.2018.07.005. Epub 2018 Jul 7.
The homeobox gene Gsx2 has previously been shown to inhibit oligodendroglial specification in dorsal lateral ganglionic eminence (dLGE) progenitors of the ventral telencephalon. The precocious specification of oligodendrocyte progenitor cells (OPCs) observed in Gsx2 mutants, however, is transient and begins to normalize by late stages of embryogenesis. Interestingly, this normalization correlates with the expansion of Gsx1, a close homolog of Gsx2, in a subset of progenitors in the Gsx2 mutant LGE. Here, we interrogated the mechanisms underlying oligodendroglial specification in Gsx2 mutants in relation to Gsx1. We found that Gsx1/2 double mutant embryos exhibit a more robust expansion of Olig2 cells (i.e. OPCs) in the subventricular zone (SVZ) of the dLGE than Gsx2 mutants. Moreover, misexpression of Gsx1 throughout telencephalic VZ progenitors from E15 and onward resulted in a significant reduction of cortical OPCs. These results demonstrate redundant roles of Gsx1 and Gsx2 in suppressing early OPC specification in LGE VZ progenitors. However, Gsx1/2 mutants did not show a significant increase in adjacent cortical OPCs at later stages compared to Gsx2 mutants. This is likely due to reduced proliferation of OPCs within the SVZ of the Gsx1/2 double mutant LGE, suggesting a novel role for Gsx1 in expansion of migrating OPCs in the ventral telencephalon. We further investigated the glial specification mechanisms downstream of Gsx2 by generating Olig2/Gsx2 double mutants. Consistent with the known essential role for Olig2 in OPC specification, ectopic production of cortical OPCs observed in Gsx2 mutants disappeared in Olig2/Gsx2 double mutants. These mutants, however, maintained the expanded expression of gliogenic markers Zbtb20 and Bcan in the VZ of the LGE similarly to Gsx2 single mutants, suggesting that Gsx2 suppresses gliogenesis via Olig2-dependent and -independent mechanisms.
同源框基因Gsx2此前已被证明可抑制端脑腹侧背外侧神经节隆起（dLGE）祖细胞中的少突胶质细胞分化。然而，在Gsx2突变体中观察到的少突胶质细胞祖细胞（OPC）过早分化是短暂的，在胚胎发育后期开始恢复正常。有趣的是，这种恢复正常与Gsx1（Gsx2的一个紧密同源物）在Gsx2突变体LGE中一部分祖细胞中的扩增相关。在这里，我们研究了Gsx2突变体中与Gsx1相关的少突胶质细胞分化的潜在机制。我们发现，Gsx1/2双突变胚胎在dLGE的脑室下区（SVZ）中Olig2细胞（即OPC）的扩增比Gsx2突变体更强烈。此外，从E15及以后在整个端脑VZ祖细胞中错误表达Gsx1导致皮质OPC显著减少。这些结果表明Gsx1和Gsx2在抑制LGE VZ祖细胞早期OPC分化中具有冗余作用。然而，与Gsx2突变体相比，Gsx1/2突变体在后期相邻皮质OPC中没有显示出显著增加。这可能是由于Gsx1/2双突变LGE的SVZ内OPC增殖减少，表明Gsx1在腹侧端脑迁移OPC的扩增中具有新作用。我们通过生成Olig2/Gsx2双突变体进一步研究了Gsx2下游的胶质细胞分化机制。与Olig2在OPC分化中的已知重要作用一致，在Gsx2突变体中观察到的皮质OPC异位产生在Olig2/Gsx2双突变体中消失。然而，这些突变体与Gsx2单突变体类似，在LGE的VZ中维持了胶质生成标记Zbtb20和Bcan的扩增表达，表明Gsx2通过Olig2依赖和非依赖机制抑制胶质生成。
