Wang, Ruoxu; (2024) Investigating the Regulation and Role of Translation Initiation in Stem Cell Fate Determination in the Drosophila Testis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. Research to date has focused mostly on transcriptional and epigenetic regulation of stem cell fate. However, discrepancies between the transcriptomes and translatomes of stem cells indicate that there is post-transcriptional control of cell identity. Here, I use the Drosophila testis as a model to study how translation initiation is regulated to control cell fate decisions in stem cells. The testis niche, called the hub, activates JAK/STAT signalling in surrounding stem cells and supports their self-renewal. Two stem cell populations reside at the niche: germline stem cells (GSCs) and somatic cyst stem cells (CySCs). I focus on the mechanisms controlling CySC self-renewal. I show that global translation rates change during normal CySC differentiation and that they depend on self-renewal signals from the niche. Since translation is mainly regulated at the initiation step, I tested whether initiation factors (eIFs) could influence stem cell behaviour. I found that different initiation factors are required for self-renewal or differentiation, indicating that translation initiation is regulated to determine cell fate. I identify a potential mechanism for this regulation, as one initiation factor, eIF3d1, was required for self-renewal. eIF3d1 is important for the interaction between eIF4F and eIF3 in a manner that depends on phosphorylation by Casein Kinase 2 (CK2), suggesting a model by which initiation can switch to a eIF4F-independent mechanism. I show that CK2 loss phenocopies loss of eIFs required for self-renewal and could be rescued by over-expression of eIF3d1, but not by eIF3d1 in which CK2 phosphorylation sites were mutated. Finally, I showed that CK2 and translation act downstream of the self-renewal pathway JAK/STAT and can rescue loss of JAK/STAT activity. In sum, my work establishes how self-renewal signals regulate translation initiation to control stem cell fate through selective translation of mRNAs.

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