Cholfin Jeremy A, Rubenstein John L R
Medical Scientist Training Program, University of California, San Francisco, San Francisco, California 94143-2611, USA.
J Comp Neurol. 2008 Jul 10;509(2):144-55. doi: 10.1002/cne.21709.
The frontal cortex (FC) plays a major role in cognition, movement and behavior. However, little is known about the genetic mechanisms that govern its development. We recently described a panel of gene expression markers that delineate neonatal FC subdivisions and identified FC regionalization defects in Fgf17-/- mutant mice (Cholfin and Rubenstein [2007] Proc. Natl. Acad. Sci. U. S. A. [in press]). In the present study, we applied this FC gene expression panel to examine regionalization phenotypes in Fgf8(neo/neo), Emx2-/-, and Emx2-/-;Fgf17-/- newborn mice. We report that Fgf8, Fgf17 and Emx2 play distinct roles in the molecular regionalization of FC subdivisions. The changes in regionalization are presaged by differential effects of rostral patterning center Fgf8 and Fgf17 signaling on the rostral cortical neuroepithelium, revealed by altered expression of Spry1, Spry2, and "rostral" transcription factors Er81, Erm, Pea3, and Sp8. We used Emx2-/-;Fgf17-/- double mutants to provide direct evidence that Emx2 and Fgf17 antagonistically regulate the expression of Erm, Pea3, and Er81 in the rostral cortical neuroepithelium and FC regionalization. We have integrated our results to propose a model for how fibroblast growth factors regulate FC patterning through regulation of regional transcription factor expression within the FC anlage.
额叶皮质（FC）在认知、运动和行为中起主要作用。然而，对于其发育所涉及的遗传机制却知之甚少。我们最近描述了一组基因表达标记，可描绘新生儿FC的亚区，并在Fgf17-/-突变小鼠中鉴定出FC区域化缺陷（Cholfin和Rubenstein [2007]《美国国家科学院院刊》[即将发表]）。在本研究中，我们应用该FC基因表达组来检测Fgf8(neo/neo)、Emx2-/-和Emx2-/-;Fgf17-/-新生小鼠的区域化表型。我们报告Fgf8、Fgf17和Emx2在FC亚区的分子区域化中发挥不同作用。区域化的变化由头端模式中心Fgf8和Fgf17信号对头端皮质神经上皮的不同影响所预示，这通过Spry1、Spry2以及“头端”转录因子Er81、Erm、Pea3和Sp8表达的改变得以揭示。我们使用Emx2-/-;Fgf17-/-双突变体提供直接证据，证明Emx2和Fgf17在头端皮质神经上皮和FC区域化中拮抗调节Erm、Pea3和Er81的表达。我们整合了研究结果，提出了一个关于成纤维细胞生长因子如何通过调节FC原基内区域转录因子的表达来调控FC模式形成的模型。
