Prager Angela, Hagenlocher Cathrin, Ott Tim, Schambony Alexandra, Feistel Kerstin
University of Hohenheim, Institute of Zoology, Garbenstr. 30, 70599 Stuttgart, Germany.
Friedrich-Alexander University Erlangen-Nuremberg, Developmental Biology, Biology Department, Staudtstr. 5, 91058 Erlangen, Germany.
Dev Biol. 2017 Oct 1;430(1):188-201. doi: 10.1016/j.ydbio.2017.07.020. Epub 2017 Aug 1.
Development of the central nervous system requires orchestration of morphogenetic processes which drive elevation and apposition of the neural folds and their fusion into a neural tube. The newly formed tube gives rise to the brain in anterior regions and continues to develop into the spinal cord posteriorly. Conspicuous differences between the anterior and posterior neural tube become visible already during neural tube closure (NTC). Planar cell polarity (PCP)-mediated convergent extension (CE) movements are restricted to the posterior neural plate, i.e. hindbrain and spinal cord, where they propagate neural fold apposition. The lack of CE in the anterior neural plate correlates with a much slower mode of neural fold apposition anteriorly. The morphogenetic processes driving anterior NTC have not been addressed in detail. Here, we report a novel role for the breast cancer susceptibility gene and microtubule (MT) binding protein Hmmr (Hyaluronan-mediated motility receptor, RHAMM) in anterior neurulation and forebrain development in Xenopus laevis. Loss of hmmr function resulted in a lack of telencephalic hemisphere separation, arising from defective roof plate formation, which in turn was caused by impaired neural tissue narrowing. hmmr regulated polarization of neural cells, a function which was dependent on the MT binding domains. hmmr cooperated with the core PCP component vangl2 in regulating cell polarity and neural morphogenesis. Disrupted cell polarization and elongation in hmmr and vangl2 morphants prevented radial intercalation (RI), a cell behavior essential for neural morphogenesis. Our results pinpoint a novel role of hmmr in anterior neural development and support the notion that RI is a major driving force for anterior neurulation and forebrain morphogenesis.
中枢神经系统的发育需要协调形态发生过程，这些过程驱动神经褶的隆起、并置以及它们融合形成神经管。新形成的神经管在前部区域发育成脑，在后部区域继续发育成脊髓。在神经管闭合（NTC）期间，神经管前部和后部之间的显著差异就已经可见。平面细胞极性（PCP）介导的汇聚延伸（CE）运动仅限于神经板后部，即后脑和脊髓，在那里它们促进神经褶并置。神经板前部缺乏CE与前部神经褶并置的速度慢得多有关。驱动前部NTC的形态发生过程尚未得到详细研究。在这里，我们报道了乳腺癌易感基因和微管（MT）结合蛋白Hmmr（透明质酸介导的运动受体，RHAMM）在非洲爪蟾前部神经胚形成和前脑发育中的新作用。Hmmr功能丧失导致端脑半球分离缺失，这是由于顶板形成缺陷引起的，而顶板形成缺陷又是由神经组织变窄受损导致的。Hmmr调节神经细胞的极化，这一功能依赖于MT结合结构域。Hmmr与核心PCP成分vangl2协同调节细胞极性和神经形态发生。Hmmr和vangl2突变体中细胞极化和伸长的破坏阻止了径向插入（RI），这是神经形态发生所必需的一种细胞行为。我们的结果确定了Hmmr在神经前部发育中的新作用，并支持RI是神经前部形成和前脑形态发生的主要驱动力这一观点。
