The Institute of Biochemistry and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel.
Dev Biol. 2012 Apr 15;364(2):162-77. doi: 10.1016/j.ydbio.2012.01.028. Epub 2012 Feb 8.
This study determined the role of MMP9/gelatinase B during the migration onset of Neural Crest Cells (NCC) in avian embryos. NCC are neuroepithelial progenitors that convert into mesenchyme and migrate along defined paths throughout the embryo. To engage in migration, NCC loose cell contacts, detach from the neural tube and invade the surrounding environment. Multiple signals and transcription factors that regulate these events have been identified. Nevertheless, little is known regarding effectors that act downstream to execute the actual NCC migration. Matrix metalloproteinases (MMPs) compose a large family of enzymes whose principal substrates are basement membranes, adhesion proteins and the extracellular matrix (ECM) components. A major subgroup of MMPs, the gelatinases (MMP9 and 2) are central to many adult physiological and pathological processes, such as tumor metastasis and angiogenesis, in which cell-cell and cell-matrix contacts are degraded to allow migration. As NCC undergo similar processes during development, we hypothesized that MMP9 may also promote the migration of NCC. MMP9 was found to be expressed in delaminating and migrating NCC of both cranial and trunk axial levels. Blocking MMP9 resulted in a dramatic inhibition of NCC delamination and migration, without perturbing specification or survival. This inhibition occurred at regions containing both premigratory and migrating cells, indicative for the central role of MMP9 in executing the detachment of NCC from the neural tube as well as their migration. Conversely, excess MMP9 enhanced mesenchymalization and delamination of NCC and accelerated progenitors to undergo precocious migration. Examination of the mechanistic activity of MMP9 revealed its capability to degrade the adhesion molecule N-cadherin as well as the basement-membrane protein laminin within or around NCC, respectively. Altogether, our study reveals MMP9 as a novel effector which is required for NCC delamination and migration.
本研究旨在确定 MMP9/明胶酶 B 在禽类胚胎神经嵴细胞（NCC）迁移起始中的作用。NCC 是神经上皮前体细胞，可转化为间质细胞，并沿胚胎中的特定路径迁移。为了进行迁移，NCC 会失去细胞间的联系，从神经管上脱离并侵入周围环境。已经确定了多种信号和转录因子来调节这些事件。然而，对于作为下游效应物来执行实际 NCC 迁移的因子知之甚少。基质金属蛋白酶（MMPs）是一个庞大的酶家族，其主要底物是基底膜、黏附蛋白和细胞外基质（ECM）成分。MMPs 的一个主要亚群，明胶酶（MMP9 和 2）在许多成人的生理和病理过程中起核心作用，如肿瘤转移和血管生成，其中细胞-细胞和细胞-基质的接触被降解以允许迁移。由于 NCC 在发育过程中经历类似的过程，我们假设 MMP9 也可能促进 NCC 的迁移。MMP9 在颅侧和轴性躯干水平的脱层和迁移的 NCC 中表达。阻断 MMP9 导致 NCC 脱层和迁移明显受到抑制，而不会干扰其特化或存活。这种抑制发生在含有前迁移和迁移细胞的区域，表明 MMP9 在执行 NCC 从神经管上脱离以及其迁移中的核心作用。相反，过量的 MMP9 增强了 NCC 的间质化和脱层，并加速了前体细胞过早迁移。对 MMP9 的机制活性的检查表明，它能够降解黏附分子 N-钙黏蛋白以及 NCC 内或周围的基底膜蛋白层粘连蛋白。总之，我们的研究揭示了 MMP9 作为一种新型效应物，是 NCC 脱层和迁移所必需的。
