Gene Regulation Group, IBMC - Instituto de Biologia Celular e Molecular, Porto, Portugal.
Gene Regulation Group, IBMC - Instituto de Biologia Celular e Molecular, Porto, Portugal; Glial Cell Biology Group, IBMC - Instituto de Biologia Celular e Molecular, Porto, Portugal.
Biochim Biophys Acta Gene Regul Mech. 2017 Jun;1860(6):685-694. doi: 10.1016/j.bbagrm.2017.03.002. Epub 2017 Mar 6.
The differential expression of mRNAs containing tandem alternative 3' UTRs, achieved by mechanisms of alternative polyadenylation and post-transcriptional regulation, has been correlated with a variety of cellular states. In differentiated cells and brain tissues there is a general use of distal polyadenylation signals, originating mRNAs with longer 3' UTRs, in contrast with proliferating cells and other tissues such as testis, where most mRNAs contain shorter 3' UTRs. Although cell type and state are relevant in many biological processes, how these mechanisms occur in specific brain cell types is still poorly understood. Rac1 is a member of the Rho family of small GTPases with essential roles in multiple cellular processes, including cell differentiation and axonal growth. Here we used different brain cell types and tissues, including oligodendrocytes, microglia, astrocytes, cortical and hippocampal neurons, and optical nerve, to show that classical Rho GTPases express mRNAs with alternative 3' UTRs differently, by gene- and cell- specific mechanisms. In particular, we show that Rac1 originate mRNA isoforms with longer 3' UTRs specifically during neurite growth of cortical, but not hippocampal neurons. Furthermore, we demonstrate that the longest Rac1 3' UTR is necessary for driving the mRNA to the neurites, and also for neurite outgrowth in cortical neurons. Our results indicate that the expression of Rac1 longer 3' UTR is a gene and cell-type specific mechanism in the brain, with a new physiological function in cortical neuron differentiation.
串联的可变 3'UTR 中 mRNA 的差异表达，通过可变多聚腺苷酸化和转录后调控的机制，与多种细胞状态相关。在分化细胞和脑组织中，普遍使用来自远端多聚腺苷酸化信号的可变多聚腺苷酸化，产生具有更长 3'UTR 的 mRNA，而在增殖细胞和其他组织（如睾丸）中，大多数 mRNA 含有更短的 3'UTR。尽管细胞类型和状态在许多生物学过程中很重要，但这些机制在特定的脑细胞类型中是如何发生的仍知之甚少。Rac1 是 Rho 家族小 GTPases 的成员，在多种细胞过程中发挥着重要作用，包括细胞分化和轴突生长。在这里，我们使用了不同的脑细胞类型和组织，包括少突胶质细胞、小胶质细胞、星形胶质细胞、皮质和海马神经元以及视神经，表明经典的 Rho GTPases 通过基因和细胞特异性机制以不同的方式表达可变 3'UTR 的 mRNAs。特别是，我们表明 Rac1 在皮质神经元而不是海马神经元的轴突生长过程中特异性地产生具有更长 3'UTR 的 mRNA 异构体。此外，我们证明最长的 Rac1 3'UTR 是将 mRNA 驱动到轴突中以及在皮质神经元中促进轴突生长所必需的。我们的结果表明，Rac1 更长 3'UTR 的表达是大脑中基因和细胞类型特异性的机制，在皮质神经元分化中具有新的生理功能。
