TGF-β Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth

Retinal axon specification and growth are critically sensitive to the dosage of numerous signaling molecules and transcription factors. Subtle variations in the expression levels of key molecules may result in a variety of axonal growth anomalies. miR-181a and miR-181b are two eye-enriched microRNAs whose inactivation in medaka fish leads to alterations of the proper establishment of connectivity and function in the visual system. miR-181a/b are fundamental regulators of MAPK signaling and their role in retinal axon growth and specification is just beginning to be elucidated. Here we demonstrate that miR-181a/b are key nodes in the interplay between TGF-β and MAPK/ERK within the functional pathways that control retinal axon specification and growth. Using a variety of in vivo and in vitro approaches in medaka fish, we demonstrate that TGF-β signaling controls the miR-181/ERK regulatory network, which in turn strengthens the TGF-β-mediated regulation of RhoA degradation. Significantly, these data uncover the role of TGF-β signaling in vivo, for the first time, in defining the correct wiring and assembly of functional retina neural circuits and further highlight miR-181a/b as key factors in axon specification and growth.视网膜轴突特化与生长对众多信号分子及转录因子的剂量具有严格的敏感性。关键分子表达水平的细微波动，可引发多种轴突生长异常表型。miR-181a与miR-181b是两类眼富集型微小RNA（microRNA），在青鳉鱼中对其进行功能失活后，会导致视觉系统连接与功能的正常建立出现异常。miR-181a/b是丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路的核心调控因子，其在视网膜轴突特化与生长中的作用才刚刚被学界阐明。本研究证实，miR-181a/b是调控视网膜轴突特化与生长的功能通路中，转化生长因子β（transforming growth factor β，TGF-β）与MAPK/ERK之间相互调控的关键节点。本研究通过在青鳉鱼中开展多种体内（in vivo）与体外（in vitro）实验，证实转化生长因子β信号通路可调控miR-181/ERK调控网络，而该网络又能增强转化生长因子β介导的RhoA蛋白降解过程。值得注意的是，本研究首次在体内揭示了转化生长因子β信号通路在调控视网膜功能性神经环路正确布线与组装中的作用，并进一步凸显miR-181a/b作为轴突特化与生长关键调控因子的重要地位。