Much focus has been given to transcriptional control of gene expression as the key determinant of stem cell fate and tissue development, with the dogma being that translation of the resulting mRNA species is a passive event. Intuitively, impaired ribosome function should (and frequently does) result in reduced tissue growth and stunted development. However, studies from both Drosophila, zebrafish and a range of human disease states suggests that a reduced level of the protein building blocks of the ribosome (the ribosomal proteins, RPs) can, counter-intuitively, drive tissue overgrowth. Utilizing Drosophila genetics, our lab decrypted part of the underlying mechanism; demonstrating global reduction of certain RPs can drive tissue overgrowth cell extrinsically as a consequence of reduced growth of the hormone secreting tissue, the prothoracic gland and defective hormone signalling (Lin et al, PLoS Genetics, 2011). More intriguingly, our unpublished data indicates that tissue-specific depletion of RPs can drive tissue overgrowth intrinsically.

Here we will present data demonstrating that tissue specific depletion of certain RPs (RPs19 and s24) in the Drosophila hematopoietic organ (the lymph gland) disrupts stem cell maintenance and, paradoxically, drives tissue overgrowth. Interestingly, knockdown of RPs19 and RPs24 differentially altered stem and progenitor cell differentiation, which suggests ribosomes might actively determine cell fate by modulating the classes of transcripts translated. Mass Spec data from the RP deficient lymph glands revealed increased protein abundance for several factors previously implicated in driving developmental programs of growth and differentiation, including master transcriptional regulators and chromatin remodeling machinery. As RNA-Seq revealed mRNA transcript levels for these factors were unchanged, we hypothesise that their defective translation underlies the stem cell fate defects and tissue overgrowth. We are currently testing whether increased abundance of our putative translational targets is necessary for overgrowth associated with RP depletion .