Department of Ophthalmology and Visual Sciences, University of Michigan, W, K, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105-0714, USA.
Neural Dev. 2012 Oct 30;7:33. doi: 10.1186/1749-8104-7-33.
Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish.
The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype.
These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins.
中期因子是一种在发育过程中在许多组织中表达的小肝素结合生长因子。哺乳动物中独特的中期因子基因在斑马鱼中有两个旁系同源物：中期因子-a（mdka）和中期因子-b（mdkb）。在斑马鱼视网膜中，在幼虫发育和成年光感受器再生过程中，mdka 在视网膜干细胞和祖细胞中表达，并作为视网膜干细胞龛的分子组成部分发挥作用。在这项研究中，使用功能丧失和条件过表达来研究 Mdka 在胚胎斑马鱼视网膜中的功能。
结果表明，在早期视网膜发育过程中，Mdka 调节细胞周期动力学。靶向敲低 Mdka 合成后，视网膜祖细胞的周期循环速度较慢，导致小眼症，细胞周期退出率降低，细胞周期退出和神经元分化的时间延迟。相比之下，Mdka 过表达导致细胞周期加速和视网膜过度生长。然而，Mdka 的功能获得并没有使细胞周期退出时间提前。鉴定潜在的 Mdka 信号通路的实验表明，Mdka 在 HLH 调节蛋白 Id2a 的上游发挥作用。基因表达分析表明 Mdka 调节 id2a 的表达，并且共注射 Mdka 形态发生素和 id2a mRNA 可挽救 Mdka 功能丧失表型。
这些数据表明，在斑马鱼中，Mdka 位于一个共同的 Id2a 途径中，以调节视网膜祖细胞的细胞周期动力学。这是第一项研究表明中期因子在视网膜发育过程中的功能，并将中期因子添加到转录调节 Id 蛋白的生长因子列表中。
