Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2013 May 10;8(5):e62959. doi: 10.1371/journal.pone.0062959. Print 2013.
Formation of the metazoan body plan requires a complex interplay of morphological changes and patterning, and central to these processes is the establishment of apical/basal cell polarity. In the developing nervous system, apical/basal cell polarity is essential for neural tube closure and maintenance of the neural stem cell population. In this report we explore how a signaling pathway important for nervous system development, Notch signaling, impacts on apical/basal cell polarity in neural differentiation. CSL(-/-) mouse embryos, which are devoid of canonical Notch signaling, demonstrated a neural tube phenotype consistent with cell polarity and convergent extension defects, including deficiencies in the restricted expression of apical polarity markers in the neuroepithelium. CSL(-/-) mouse embryonic stem (ES) cells, cultured at low density, behaved as wild-type in the establishment of neural progenitors and apical specification, though progression through rosette formation, an in vitro correlate of neurulation, required CSL for correct maintenance of rosette structure and regulation of neuronal differentiation. Similarly, acute pharmacological inhibition of Notch signaling led to the breakdown of neural rosettes and accelerated neuronal differentiation. In addition to functional Notch signaling, rosette integrity was found to require actin polymerization and Rho kinase (ROCK) activity. Disruption of rosettes through inhibition of actin polymerization or ROCK activity, however, had no effect on neuronal differentiation, indicating that rosette maintenance is not a prerequisite for normal neuronal differentiation. In conclusion, our data indicate that Notch signaling plays a role not only in differentiation, but also in organization and maintenance of polarity during development of the early nervous system.
后生动物体型的形成需要形态变化和模式形成的复杂相互作用，而这些过程的核心是建立顶端/基底细胞极性。在发育中的神经系统中，顶端/基底细胞极性对于神经管闭合和神经干细胞群体的维持至关重要。在本报告中，我们探讨了对神经系统发育很重要的信号通路，即 Notch 信号通路，如何影响神经分化中的顶端/基底细胞极性。缺乏典型 Notch 信号的 CSL(-/-) 小鼠胚胎表现出与细胞极性和收敛延伸缺陷一致的神经管表型，包括神经上皮中顶端极性标记的限制表达缺陷。在低细胞密度下培养的 CSL(-/-) 小鼠胚胎干细胞在建立神经祖细胞和顶端特化方面表现出与野生型相同的行为，尽管通过形成玫瑰花结进行体外神经发生的过程需要 CSL 来正确维持玫瑰花结结构和调节神经元分化。同样， Notch 信号的急性药理学抑制导致神经玫瑰花结的破坏和神经元分化的加速。除了功能性 Notch 信号外，玫瑰花结的完整性还需要肌动蛋白聚合和 Rho 激酶 (ROCK) 活性。然而，通过抑制肌动蛋白聚合或 ROCK 活性破坏玫瑰花结对神经元分化没有影响，表明玫瑰花结的维持不是正常神经元分化的先决条件。总之，我们的数据表明，Notch 信号不仅在分化中发挥作用，而且在早期神经系统发育过程中对极性的组织和维持也发挥作用。
