This whole story was started in 1977, when Heidemann and collegues treated the purified basal bodies with RNase A and discovered a magnificent abolishment of the aster-inducing activity¹. After that, in 1980, another study showed that microtubule nucleation and structure of the purified centrosomes were severely impaired by RNase treatment², suggesting that RNA plays a critical role in supporting the structural integrity of the microtubule-based cytoskeleton. These early findings hinted at the presence of a missing puzzle piece in understanding the intricate processes of microtubule assembly and organization^3-6.

Fast forward to the present day, our research has unveiled TubAR, a long noncoding RNA (lncRNA) that serves as the missing piece of this intricate puzzle. With high expression in the cerebellum, TubAR forms an essential RNA-protein complex with key cerebellar tubulin isotypes TUBB4A and TUBA1A, both of which are clinically associated with cerebellar and myelination defects.

Our journey commenced with the aim of identifying specific lncRNAs expressed in the cerebellum, driven by previous studies highlighting the significance of cerebellar lncRNA expression patterns⁷. Through microarrays, we identified dozens of highly expressed cerebellar lncRNAs, ultimately honing in on the top-expressed lncRNA, later named TubAR, which exhibited robust binding capacities to multiple tubulins. This discovery captured our attention, especially considering the phenotype of TubAR-deficient mice, mirroring that of TUBB4A⁸. Subsequently, our concerted efforts over several years illuminated TubAR's pivotal role in promoting TUBB4A-TUBA1A heterodimer formation and microtubule assembly, providing novel insights into RNA-mediated cytoskeletal regulation with potential implications for understanding brain function and related disorders.

In conclusion, our study transcends the traditional understanding of lncRNAs in genetic regulation and signal transduction by revealing TubAR as a structural RNA that influences cytoskeletal architecture. As we delve deeper into the structural requirements of lncRNAs in microtubule assembly, we are spurred to reassess our perceptions of cell structure formation and the diverse roles of regulatory RNAs in cellular physiology.This groundbreaking research not only sheds light on the intricate mechanisms governing microtubule assembly and organization but also underscores the profound impact of noncoding RNAs in shaping cellular structures and functions, thereby paving the way for further explorations and potential therapeutic interventions.

References:

1          Heidemann, S. R., Sander, G. & Kirschner, M. W. Evidence for a functional role of RNA in centrioles. Cell 10, 337-350 (1977). https://doi.org:10.1016/0092-8674(77)90021-6

2          Pepper, D. A. & Brinkley, B. R. Tubulin nucleation and assembly in mitotic cells: evidence for nucleic acids in kinetochores and centrosomes. Cell Motil 1, 1-15 (1980). https://doi.org:10.1002/cm.970010102

3          Blower, M. D., Nachury, M., Heald, R. & Weis, K. A Rae1-containing ribonucleoprotein complex is required for mitotic spindle assembly. Cell 121, 223-234 (2005). https://doi.org:10.1016/j.cell.2005.02.016

4          Hussain, S. et al. The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability. J Cell Biol 186, 27-40 (2009). https://doi.org:10.1083/jcb.200810180

5          Ito, K. K., Watanabe, K. & Kitagawa, D. The Emerging Role of ncRNAs and RNA-Binding Proteins in Mitotic Apparatus Formation. Noncoding RNA 6 (2020). https://doi.org:10.3390/ncrna6010013

6          Alliegro, M. C. The centrosome and spindle as a ribonucleoprotein complex. Chromosome Res 19, 367-376 (2011). https://doi.org:10.1007/s10577-011-9186-7

7          Wang, F. et al. A long noncoding RNA cluster-based genomic locus maintains proper development and visual function. Nucleic Acids Res47, 6315-6329 (2019). https://doi.org:10.1093/nar/gkz444

8          Liang, X. et al. LncRNA TubAR complexes with TUBB4A and TUBA1A to promote microtubule assembly and maintain myelination. Cell Discov 10, 54 (2024). https://doi.org:10.1038/s41421-024-00667-y