Lee S M, Danielian P S, Fritzsch B, McMahon A P
Department of Molecular and Cellular Biology, The Biolabs, Harvard University, Cambridge, MA 02138, USA.
Development. 1997 Mar;124(5):959-69. doi: 10.1242/dev.124.5.959.
The developing vertebrate mesencephalon shows a rostrocaudal gradient in the expression of a number of molecular markers and in the cytoarchitectonic differentiation of the tectum, where cells cease proliferating and differentiate in a rostral to caudal progression. Tissue grafting experiments have implicated cell signalling by the mesencephalic-metencephalic (mid-hindbrain) junction (or isthmus) in orchestrating these events. We have explored the role of Wnt-1 and FGF8 signalling in the regulation of mesencephalic polarity. Wnt-1 is expressed in the caudal mesencephalon and Fgf8 in the most rostral metencephalon. Wnt-1 regulates Fgf8 expression in the adjacent metencephalon, most likely via a secondary mesencephalic signal. Ectopic expression of Fgf8 in the mesencephalon is sufficient to activate expression of Engrailed-2 (En-2) and ELF-1, two genes normally expressed in a decreasing caudal to rostral gradient in the posterior mesencephalon. Ectopic expression of Engrailed-1 (En-1), a functionally equivalent homologue of En-2 is sufficient to activate ELF-1 expression by itself. These results indicate the existence of a molecular hierarchy in which FGF8 signalling establishes the graded expression of En-2 within the tectum. This in turn may act to specify other aspects of A-P polarity such as graded ELF-1 expression. Our studies also reveal that FGF8 is a potent mitogen within the mesencephalon: when ectopically expressed, neural precursors continue to proliferate and neurogenesis is prevented. Taken together our results suggest that FGF8 signalling from the isthmus has a key role in coordinately regulating growth and polarity in the developing mesencephalon.
发育中的脊椎动物中脑在多种分子标记的表达以及顶盖的细胞结构分化方面呈现出前后梯度，顶盖中的细胞在前后方向上依次停止增殖并分化。组织移植实验表明，中脑 - 后脑（中后脑）交界处（或峡部）的细胞信号传导参与协调这些事件。我们探讨了Wnt-1和FGF8信号在中脑极性调节中的作用。Wnt-1在中脑尾部表达，Fgf8在最靠前的后脑表达。Wnt-1最有可能通过次级中脑信号调节相邻后脑Fgf8的表达。Fgf8在中脑的异位表达足以激活Engrailed-2（En-2）和ELF-1的表达，这两个基因通常在后侧中脑以从尾到头递减的梯度表达。Engrailed-1（En-1）是En-2的功能等同同源物，其异位表达自身就足以激活ELF-1的表达。这些结果表明存在一种分子层级关系，其中FGF8信号传导在顶盖内建立了En-2的梯度表达。这反过来可能决定前后极性的其他方面，如ELF-1的梯度表达。我们的研究还表明，FGF8是中脑内一种有效的有丝分裂原：当异位表达时，神经前体细胞会持续增殖并阻止神经发生。综合我们的结果表明，来自峡部的FGF8信号传导在协调调节发育中的中脑的生长和极性方面具有关键作用。
