Hasenpusch-Theil Kerstin, Watson Julia A, Theil Thomas
Centre for Integrative Physiology, Hugh Robson Building, University of Edinburgh, EdinburghEH8 9XD, UK.
Cereb Cortex. 2017 Feb 1;27(2):1137-1148. doi: 10.1093/cercor/bhv291.
A key step in the development of the cerebral cortex is a patterning process, which subdivides the telencephalon into several molecularly distinct domains and is critical for cortical arealization. This process is dependent on a complex network of interactions between signaling molecules of the Fgf and Wnt gene families and the Gli3 transcription factor gene, but a better knowledge of the molecular basis of the interplay between these factors is required to gain a deeper understanding of the genetic circuitry underlying telencephalic patterning. Using DNA-binding and reporter gene assays, we here investigate the possibility that Gli3 and these signaling molecules interact by directly regulating each other's expression. We show that Fgf signaling is required for Wnt8b enhancer activity in the cortical hem, whereas Wnt/β-catenin signaling represses Fgf17 forebrain enhancer activity. In contrast, Fgf and Wnt/β-catenin signaling cooperate to regulate Gli3 expression. Taken together, these findings indicate that mutual interactions between Gli3, Wnt8b, and Fgf17 are crucial elements of the balance between these factors thereby conferring robustness to the patterning process. Hence, our study provides a framework for understanding the genetic circuitry underlying telencephalic patterning and how defects in this process can affect the formation of cortical areas.
大脑皮层发育的一个关键步骤是模式形成过程，该过程将端脑细分为几个分子特征不同的区域，对皮质区域化至关重要。这一过程依赖于Fgf和Wnt基因家族的信号分子与Gli3转录因子基因之间复杂的相互作用网络，但需要更深入了解这些因子之间相互作用的分子基础，才能更深入地理解端脑模式形成背后的遗传回路。我们利用DNA结合和报告基因检测，研究Gli3与这些信号分子是否通过直接调节彼此的表达而相互作用。我们发现，Fgf信号对于皮质下托中Wnt8b增强子的活性是必需的，而Wnt/β-连环蛋白信号则抑制Fgf17前脑增强子的活性。相反，Fgf和Wnt/β-连环蛋白信号协同调节Gli3的表达。综上所述，这些发现表明Gli3、Wnt8b和Fgf17之间的相互作用是这些因子之间平衡的关键因素，从而赋予模式形成过程稳健性。因此，我们的研究为理解端脑模式形成背后的遗传回路以及该过程中的缺陷如何影响皮质区域的形成提供了一个框架。
