Januschke lab discovers a protein localization mechanism behind cell fate choice

How cells position proteins, which make up most of the cells content is therefore a central problem in cell and developmental biology. The control of protein distribution is complex, but it has become clear that the localization of mRNA (the template for protein production) can influence where proteins are positioned. Local pools of mRNA can serve as spatially restricted source of the synthesis of the encoded protein. This mechanism is long-known to be important during early development, but it is now clear that localized mRNAs in the cytoplasm are rather frequent as this phenomenon has  now been found in a number of different cell types of several species. A question arising from here is whether local mRNAs always function as templates for local protein synthesis or if they can have additional functions.

The Januschke lab in Cell Development and Biology in the School have now asked the question of how localized mRNAs contribute to the production of different cell fates. They used the developing nervous system of Drosophila and analysed the contribution of mRNA localization to the mechanism that specifies two different cell fates in a single division. In this so called asymmetric cell division a stem cell divides and during this division proteins become unequally localized such that once division is complete, the resulting daughter cells receive each a set of different proteins. One daughter cell receives factors determining stem cell fate, while the other daughter cell receives proteins that instruct it to differentiate. The instruction to differentiate depends critically on an adapter protein called Miranda, which is localized asymmetrically in the stem cell in mitosis to that part of the cortex, that will be inherited by the differentiating daughter cell. How this asymmetric distribution of Miranda is controlled is not understood.

Dr. Anne Ramat in the Januschke lab now discovered that the mRNA of miranda is also asymmetrically distributed and colocalizes with Miranda protein in the stem cell. To test if the localization of the mRNA is functionally relevant, endogenous miranda mRNA was tagged with green fluorescent protein (GFP). Then GFP-specific single domain antibodies (nanobodies) fused to a particular subcellular localization domain were expressed in the stem cells to alter the localization of the mRNA. Tethering the mRNA to the opposite corner of the stem cell, to which it normally does not localize, resulted in failure of Miranda protein to localize asymmetrically. The study further suggests that the mRNA rather than serving as a local source of translation, functions as a scaffold to maintain Miranda protein asymmetrically anchored such that it is inherited only by one daughter cell. Such positive feedback between protein and its connected mRNA, might be a general principle regulating local protein concentrations in cells.