Martinez-Ferre Almudena, Lloret-Quesada Cosme, Prakash Nilima, Wurst Wolfgang, Rubenstein John L R, Martinez Salvador
Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), University of Murcia, 30120, El Palmar, Murcia, Spain.
Institute of Neurosciences, Miguel Hernández University, Spanish National Research Council, San Juan Campus, 03550, Sant Joan d'Alacant, Alicante, Spain.
Brain Struct Funct. 2016 Jul;221(6):3095-109. doi: 10.1007/s00429-015-1089-5. Epub 2015 Aug 27.
The establishment of the brain structural complexity requires a precisely orchestrated interplay between extrinsic and intrinsic signals modulating cellular mechanisms to guide neuronal differentiation. However, little is known about the nature of these signals in the diencephalon, a complex brain region that processes and relays sensory and motor information to and from the cerebral cortex and subcortical structures. Morphogenetic signals from brain organizers regulate histogenetic processes such as cellular proliferation, migration, and differentiation. Sonic hedgehog (Shh) in the key signal of the ZLI, identified as the diencephalic organizer. Fgf15, the mouse gene orthologous of human, chick, and zebrafish Fgf19, is induced by Shh signal and expressed in the diencephalic alar plate progenitors during histogenetic developmental stages. This work investigates the role of Fgf15 signal in diencephalic development. In the absence of Fgf15, the complementary expression pattern of proneural genes: Ascl1 and Nng2, is disrupted and the GABAergic thalamic cells do not differentiate; in addition dorsal thalamic progenitors failed to exit from the mitotic cycle and to differentiate into neurons. Therefore, our findings indicate that Fgf15 is the Shh downstream signal to control thalamic regionalization, neurogenesis, and neuronal differentiation by regulating the expression and mutual segregation of neurogenic and proneural regulatory genes.
脑结构复杂性的建立需要外在和内在信号之间精确协调的相互作用，这些信号调节细胞机制以引导神经元分化。然而，对于间脑（一个处理并向大脑皮层和皮层下结构传递感觉和运动信息的复杂脑区）中这些信号的本质，我们知之甚少。来自脑组织者的形态发生信号调节组织发生过程，如细胞增殖、迁移和分化。Sonic hedgehog（Shh）是ZLI的关键信号，被确定为间脑组织者。Fgf15是人类、鸡和斑马鱼Fgf19的小鼠同源基因，由Shh信号诱导，并在组织发生发育阶段在间脑翼板祖细胞中表达。这项工作研究了Fgf15信号在间脑发育中的作用。在没有Fgf15的情况下，神经前体基因Ascl1和Ngn2的互补表达模式被破坏，GABA能丘脑细胞无法分化；此外，背侧丘脑祖细胞无法退出有丝分裂周期并分化为神经元。因此，我们的研究结果表明，Fgf15是Shh下游信号，通过调节神经源性和神经前体调节基因的表达和相互分离来控制丘脑区域化、神经发生和神经元分化。
