Kapsimali Marika, Caneparo Luca, Houart Corinne, Wilson Stephen W
Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
Development. 2004 Dec;131(23):5923-33. doi: 10.1242/dev.01453.
Ventral midline cells in the neural tube form floorplate throughout most of the central nervous system (CNS) but in the anterior forebrain, they differentiate with hypothalamic identity. The signalling pathways responsible for subdivision of midline neural tissue into hypothalamic and floorplate domains are uncertain, and in this study, we have explored the role of the Wnt/Axin/beta-catenin pathway in this process. This pathway has been implicated in anteroposterior regionalisation of the dorsal neural tube but its role in patterning ventral midline tissue has not been rigorously assessed. We find that masterblind zebrafish embryos that carry a mutation in Axin1, an intracellular negative regulator of Wnt pathway activity, show an expansion of prospective floorplate coupled with a reduction of prospective hypothalamic tissue. Complementing this observation, transplantation of cells overexpressing axin1 into the prospective floorplate leads to induction of hypothalamic gene expression and suppression of floorplate marker gene expression. Axin1 is more efficient at inducing hypothalamic markers than several other Wnt pathway antagonists, and we present data suggesting that this may be due to an ability to promote Nodal signalling in addition to suppressing Wnt activity. Indeed, extracellular Wnt antagonists can promote hypothalamic gene expression when co-expressed with a modified form of Madh2 that activates Nodal signalling. These results suggest that Nodal signalling promotes the ability of cells to incorporate into ventral midline tissue, and within this tissue, antagonism of Wnt signalling promotes the acquisition of hypothalamic identity. Wnt signalling also affects patterning within the hypothalamus, suggesting that this pathway is involved in both the initial anteroposterior subdivision of ventral CNS midline fates and in the subsequent regionalisation of the hypothalamus. We suggest that by regulating the response of midline cells to signals that induce ventral fates, Axin1 and other modulators of Wnt pathway activity provide a mechanism by which cells can integrate dorsoventral and anteroposterior patterning information.
神经管中的腹侧中线细胞在中枢神经系统（CNS）的大部分区域形成底板，但在前脑前部，它们分化为具有下丘脑特征的细胞。负责将中线神经组织细分为下丘脑和底板区域的信号通路尚不清楚，在本研究中，我们探讨了Wnt/Axin/β-连环蛋白信号通路在此过程中的作用。该信号通路与背侧神经管的前后区域化有关，但其在腹侧中线组织模式形成中的作用尚未得到严格评估。我们发现，携带Axin1（Wnt信号通路活性的细胞内负调节因子）突变的masterblind斑马鱼胚胎显示出预期底板的扩展，同时预期下丘脑组织减少。与此观察结果互补的是，将过表达axin1的细胞移植到预期底板中会导致下丘脑基因表达的诱导和底板标记基因表达的抑制。Axin1在诱导下丘脑标记物方面比其他几种Wnt信号通路拮抗剂更有效，我们提供的数据表明，这可能是由于除了抑制Wnt活性外，还具有促进Nodal信号传导的能力。事实上，当与激活Nodal信号传导的Madh2修饰形式共表达时，细胞外Wnt拮抗剂可以促进下丘脑基因表达。这些结果表明，Nodal信号传导促进细胞整合到腹侧中线组织的能力，并且在该组织内，Wnt信号传导的拮抗作用促进下丘脑特征的获得。Wnt信号传导也影响下丘脑内的模式形成，表明该信号通路参与腹侧CNS中线命运的初始前后细分以及下丘脑随后的区域化。我们认为，通过调节中线细胞对诱导腹侧命运信号的反应，Axin1和Wnt信号通路活性的其他调节因子提供了一种细胞可以整合背腹和前后模式形成信息的机制。
