A tug of war between DCC and ROBO1 signaling during commissural axon guidance.
A tug of war between DCC and ROBO1 signaling during commissural axon guidance.
复制标题
在合并轴突指导期间，DCC和Robo1信号传导之间的一场战争。
DOI：
10.1016/j.celrep.2023.112455
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发表时间：
2023-05-30
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
对不断变化的环境的动态和协调的轴突反应对于建立神经连接至关重要。当连合轴突穿过中枢神经系统中线迁移时，建议它们从被吸引转变为被排斥，以便接近并随后离开中线。据推测，轴突反应中这种转变的分子机制是结直肠癌 (DCC) 中由排斥性 SLIT/ROBO1 信号传导引起的 Netrin1/Deleted 介导的吸引力的沉默。使用体内方法，包括不同 Dcc 剪接亚型的 CRISPR-Cas9 工程小鼠模型，我们在此表明，连合轴突在中线交叉期间保持对 Netrin 和 SLIT 的响应，尽管可能在数量上不同的水平。此外，全长DCC与ROBO3配合可以在体内拮抗ROBO1的排斥作用。我们建议连合轴突整合并平衡相反的 DCC 和 Roundabout (ROBO) 信号，以确保中线进入和退出期间的正确指导决策。 Dailey-Krempel 等人使用 CRISPR-Cas9 工程改造的 Dcc 同工型突变体。表明 Netrin1/DCC 和 SLIT/ROBO1 信号传导在体内调节轴突引导方面参与了类似于拔河比赛的反作用。
Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit. Using CRISPR-Cas9-engineered Dcc isoform mutants, Dailey-Krempel et al. show that Netrin1/DCC and SLIT/ROBO1 signaling are engaged in a counteraction akin to a tug of war in regulating axon guidance in vivo.
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