Department of Biology, Stanford University, Stanford, California 94305, USA.
Dev Neurobiol. 2012 Sep;72(9):1196-212. doi: 10.1002/dneu.20985. Epub 2012 Jun 21.
During neural development patterning, neurogenesis, and overall growth are highly regulated and coordinated between different brain regions. Here, we show that primary cilia and the regulation of Gli activity are necessary for the normal expansion of the cerebral cortex. We show that loss of Kif3a, an important functional component of primary cilia, leads to the degeneration of primary cilia, marked overgrowth of the cortex, and altered cell cycle kinetics within cortical progenitors. The G1 phase of the cell cycle is shortened through a mechanism likely involving reduced Gli3 activity and a resulting increase in expression of cyclin D1 and Fgf15. The defects in Gli3 activity alone are sufficient to accelerate cell cycle kinetics and cause the molecular changes seen in brains that lack cilia. Finally, we show that levels of full-length and repressor Gli3 proteins are tightly regulated during normal development and correlate with changes in expression of two known Shh-target genes, CyclinD1 and Fgf15, and with the normal lengthening of the cell cycle during corticogenesis. These data suggest that Gli3 activity is regulated through the primary cilium to control cell cycle length in the cortex and thus determine cortical size.
在神经发育模式形成、神经发生和整体生长过程中，不同脑区之间的高度调节和协调。在这里，我们表明，初级纤毛和 Gli 活性的调节对于大脑皮层的正常扩展是必要的。我们发现，重要的初级纤毛功能成分 Kif3a 的缺失会导致初级纤毛退化、皮层过度生长以及皮层祖细胞中细胞周期动力学的改变。细胞周期的 G1 期通过一种可能涉及减少 Gli3 活性的机制缩短，从而导致细胞周期蛋白 D1 和 Fgf15 的表达增加。Gli3 活性的缺陷本身足以加速细胞周期动力学，并导致缺乏纤毛的大脑中出现的分子变化。最后，我们表明，全长和抑制性 Gli3 蛋白的水平在正常发育过程中受到严格调节，与两个已知的 Shh 靶基因，CyclinD1 和 Fgf15 的表达变化以及皮质发生过程中细胞周期的正常延长相关。这些数据表明，Gli3 活性通过初级纤毛调节来控制皮层中的细胞周期长度，从而决定皮层的大小。
