The unexpected turns that life can take are often appealing, but for cells, their fates must be tightly controlled. To ensure this, the same mechanism is used time and again to distinguish between two cell types — transcriptional regulation, leading to differential gene expression. A less common mechanism is now highlighted by Okabe and colleagues in Nature, who show that, for one neuronal cell type, this decision is made at the next step — translational repression.

Okabe and colleagues focused on a Drosophila neural precursor that divides asymmetrically to produce one neuronal and one non-neuronal cell type. The key determinant, Tramtrack69 (Ttk69), is necessary and sufficient to specify non-neuronal identity, and Notch signalling is known to act upstream of Ttk69. But how does it achieve this?

The authors found that ttk69 mRNA levels are similar in both cells, leading them to propose that its activity is regulated post-transcriptionally. From genetic analysis, a good candidate for regulating ttk69 mRNA is Musashi (Msi), which encodes an RNA-binding protein. To test this possibility, the authors identified the target sequences that Msi binds and confirmed their presence in the 3′ untranslated region (3′UTR) of ttk69 mRNA. Using a gel mobility-shift assay, they then showed that Msi binds to these sequences.

To address the significance of this binding, they used a translational reporter system in S2 cells. And they found that Msi inhibits the translation of ttk69 mRNA by binding to the 3′UTR.

One curiosity is that Msi is present in both both cell types. So how does the neuronal cell escape repression of Ttk69? The authors predict that Notch signalling blocks Msi activity. In the cell where Notch signalling is blocked, then, Msi is free to repress translation of Ttk69. Given that mammalian homologues of both Msi and Notch are present in the vertebrate nervous system, they speculate that cell-type-specific translation repression might be an evolutionarily conserved mechanism.