Child Study Center, Department of Neurobiology, and Kavli Institute for Neuroscience, Yale University, New Haven, Connecticut 06520, USA.
J Neurosci. 2013 Jun 26;33(26):10802-14. doi: 10.1523/JNEUROSCI.3621-12.2013.
Gyrification allows an expanded cortex with greater functionality to fit into a smaller cranium. However, the mechanisms of gyrus formation have been elusive. We show that ventricular injection of FGF2 protein at embryonic day 11.5-before neurogenesis and before the formation of intrahemispheric axonal connections-altered the overall size and shape of the cortex and induced the formation of prominent, bilateral gyri and sulci in the rostrolateral neocortex. We show increased tangential growth of the rostral ventricular zone (VZ) but decreased Wnt3a and Lef1 expression in the cortical hem and adjacent hippocampal promordium and consequent impaired growth of the caudal cortical primordium, including the hippocampus. At the same time, we observed ectopic Er81 expression, increased proliferation of Tbr2-expressing (Tbr2(+)) intermediate neuronal progenitors (INPs), and elevated Tbr1(+) neurogenesis in the regions that undergo gyrification, indicating region-specific actions of FGF2 on the VZ and subventricular zone (SVZ). However, the relative number of basal radial glia-recently proposed to be important in gyrification-appeared to be unchanged. These findings are consistent with the hypothesis that increased radial unit production together with rapid SVZ growth and heightened localized neurogenesis can cause cortical gyrification in lissencephalic species. These data also suggest that the position of cortical gyri can be molecularly specified in mice. In contrast, a different ligand, FGF8b, elicited surface area expansion throughout the cortical primordium but no gyrification. Our findings demonstrate that individual members of the diverse Fgf gene family differentially regulate global as well as regional cortical growth rates while maintaining cortical layer structure.
脑回形成的机制一直难以捉摸。我们发现，在神经发生之前，即在半球内轴突连接形成之前，在胚胎第 11.5 天向脑室注射 FGF2 蛋白，改变了皮质的整体大小和形状，并在前外侧新皮质诱导了明显的双侧脑回和脑沟的形成。我们发现，头侧脑室区（VZ）的切向生长增加，但皮质半球和相邻海马原基中的 Wnt3a 和 Lef1 表达减少，导致尾侧皮质原基（包括海马体）的生长受损。同时，我们观察到 Er81 表达异位，Tbr2 表达（Tbr2(+）中间神经元祖细胞（INP）增殖增加，以及在经历脑回形成的区域中 Tbr1(+)神经发生增加，表明 FGF2 对 VZ 和室下区（SVZ）具有区域特异性作用。然而，基底放射状胶质细胞的相对数量（最近被提出对脑回形成很重要）似乎没有变化。这些发现与以下假设一致，即增加放射状单位的产生，加上 SVZ 的快速生长和局部神经发生的增加，可导致无脑回物种的皮质脑回形成。这些数据还表明，在小鼠中，皮质脑回的位置可以在分子上确定。相比之下，另一种配体 FGF8b 可使整个皮质原基的表面积扩大，但不会形成脑回。我们的研究结果表明，多样化的 Fgf 基因家族的各个成员可在维持皮质层结构的同时，差异调节整体和局部皮质生长速度。
