Control of cell migration and tissue morphogenesis via modulation of mRNA localisation.

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Tight control of cell migration is fundamental to coordinating tissue movement and morphogenesis, and is frequently dysregulated in diseases such as cancer. Hence, to achieve predictable control of cell migration would have clear therapeutic benefits, both in tackling disease and facilitating robust tissue repair/regeneration. The Herbert lab employs a highly multidisciplinary approach to investigate mechanisms of tissue formation in-vivo and recently revealed that the subcellular polarisation of certain mRNAs to the front of migrating cells acts as a 'molecular compass' that orients their migration and tissue movement1. In particular, we uncovered that this mRNA localisation is driven by consensus 'targeting-motifs' residing in the 3'UTRs of these transcripts. Moreover, that CRISPR-mediated excision of this motif from just one transcript, encoding RAB13, was sufficient to eradicate RAB13 mRNA polarisation and perturb motile cell behaviour. Likewise, excision of this motif in-vivo in the zebrafish model was sufficient to drive disorganised blood vessel morphogenesis. In recent unpublished work we identified additional polarised mRNAs that modulate cell migration, for example, via control of mitochondria positioning, further highlighting the key functional importance of mRNA localisation. Yet, we still do not know (1) the mechanisms by which mRNA polarisation is controlled during cell migration, (2) how this mRNA targeting ultimately regulates protein function, and (3) if this phenomenon can be exploited to achieve predictable control of tissue movement and morphogenesis in-vivo.