Functional and evolutionary impact of neural-specific exons and microexons in vertebrates

Functional and evolutionary impact of neural-specific exons and microexons in vertebrates

Lab members: Jon Permanyer, Laura López-Blanch, Antonio Torres-Méndez, Javier Tapial, Yamile Márquez, Beth Kita.

Funding: ERC Starting Grant, EMBO, MINECO, CRG

Mirroring their unparalleled morphological and cellular complexity, vertebrate brains show the highest levels of regulated alternative splicing known in nature. However, the functions of most of these alternative transcripts, and the evolutionary impact that the increased transcriptional complexity has had on the evolution of the vertebrate brain are still widely unexplored.

 

Microexons (Irimia et al, Cell 2014)

In this research line, we are investigating the functions and evolutionary impact of neural-specific alternative splicing in vertebrates. In particular, we focus on microexons, tiny exons between 3-27 nucleotides long that show striking switches during neuronal regulation and unmatched evolutionary conservation across vertebrates. We aim to understand (i) the evolutionary origins of microexons and their span across metazoan nervous systems, (ii) the molecular bases and conservation of their exquisite neuronal regulation, (iii) their impact on protein structures and protein-protein interactions, (iv) their roles during vertebrate embryo development, and (v) their potential causal links with autism spectrum disorder.

 

Protein microsurgery by microexons (Alexander Weiss)

 

To achieve these goals, we apply a combination of bioinformatics and high-throughput transcriptomic analyses in multiple vertebrate and invertebrate species, experimental manipulation in models species using CRISPR-Cas9 technology for genome editing, and systems-level analysis and modelling of proteins structures and interaction networks.

Related publications:

  • Gueroussov, S., Gonatopoulos-Pournatzis, T., Irimia, M., Raj, B., Lin, Z.Y., Gingras, A.C., Blencowe, B.J. An alternative splicing event amplifies evolutionary differences between vertebrates. Science, 349:868-73.
  • Quesnel-Vallières, M., Irimia, M., Cordes, S.P., Blencowe, B.B. Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development. Genes Dev., 29(7):746-59.
  • Irimia, M., Weatheritt, R.J., Ellis, J., Parikshak, N.N., Gonatopoulos-Pournatzis, T., Babor, M., Quesnel-Vallières, M., Tapial, J., Raj, B., O'Hanlon, D., Barrios-Rodiles, M., Sternberg, M.J.E., Cordes, S.P., Roth, F.P., Wrana, J.L., Geschwind, D.H., Blencowe, B.B. (2014). A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell, 159:1511-23.
  • Braunschweig, U., Barbosa-Morais, N.L., Pan, Q., Nachman, E., Alipahani, B., Gonatopoulos-Pournatzis, T., Frey, B., Irimia, M., Blencowe, B.J. (2014). Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res. 24:1774-86.
  • Raj, B., Irimia, M., Braunschweig, U., Sterne-Weiler, T., O'Hanlon, D., Lin, Z.Y., Chen, G.I., Easton, L.E., Ule, J., Gingras, A.C., Eyras, E., Blencowe, B.J. (2014). A Global Regulatory Mechanism for Activating an Exon Network Required for Neurogenesis. Mol. Cell, 56(1):90-103.
  • Nagalski, A., Irimia, M., Szewczyk, L., Ferran, J.L., Misztal, K., Kuznicki, J., Wisniewska, M.B. (2013). Postnatal isoform switch and protein localization of LEF1 and TCF7L2 transcription factors in cortical, thalamic, and mesencephalic regions of the adult mouse brain. Brain Struct Funct, 218(6):1531-49.