Majumder Tanushree, Khot Bhakti, Suriyaarachchi Harindi, Nathan Anagaa, Liu Guofa
Department of Biological Sciences, University of Toledo, Toledo, OH 43606.
Mol Biol Cell. 2025 Apr 1;36(4):ar50. doi: 10.1091/mbc.E24-12-0534. Epub 2025 Feb 28.
In the developing spinal cord, translational repression of Robo1 expression by microRNA-92 (miR-92) in precrossing commissural axons (CAs) inhibits Slit/Robo1-mediated repulsion facilitating commissural axon projection and midline crossing; however, the regulatory mechanisms governing miR-92 expression in the developing commissural neurons are currently lacking. Here, we propose that the transcription factor MYC regulates miR-92 expression in the developing spinal cord (of either sex) to control Robo1 levels in precrossing CAs, modulating Slit/Robo1-mediated repulsion and midline crossing. MYC, miR-92, and Robo1 are differentially expressed in the developing chicken spinal cord. MYC binds to the promoter region upstream of the gga-miR-92 gene . MYC knockdown dramatically decreases miR-92 expression and increases chicken Robo1 (cRobo1) levels. In contrast, overexpression of MYC significantly induces miR-92 expression and reduces cRobo1 levels. MYC knockdown or overexpression results in significant inhibition or induction of miR-92 activity in the developing chicken spinal cord, respectively. Disruption of the MYC-dependent regulation of the miR-92-cRobo1 axis affects Slit2-mediated CA growth cone collapse and impairs CA projection and midline crossing . These results elucidate the role of the MYC-miR-92-cRobo1 axis in Slit2/Robo1-mediated CA repulsion and midline crossing.
在发育中的脊髓中，前连合轴突（CA）中的微小RNA-92（miR-92）对Robo1表达的翻译抑制作用可抑制Slit/Robo1介导的排斥反应，从而促进连合轴突投射和中线交叉；然而，目前尚缺乏对发育中的连合神经元中miR-92表达调控机制的研究。在此，我们提出转录因子MYC可调节发育中（无论性别）脊髓中的miR-92表达，以控制前连合轴突中Robo1的水平，调节Slit/Robo1介导的排斥反应和中线交叉。MYC、miR-92和Robo1在发育中的鸡脊髓中差异表达。MYC与gga-miR-92基因上游的启动子区域结合。敲低MYC可显著降低miR-92表达，并增加鸡Robo1（cRobo1）的水平。相反，过表达MYC可显著诱导miR-92表达，并降低cRobo1水平。敲低或过表达MYC分别导致发育中的鸡脊髓中miR-92活性受到显著抑制或诱导。破坏MYC对miR-92-cRobo1轴的依赖性调节会影响Slit2介导的CA生长锥塌陷，并损害CA投射和中线交叉。这些结果阐明了MYC-miR-92-cRobo1轴在Slit2/Robo1介导的CA排斥反应和中线交叉中的作用。
