Abstract
To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult Caenorhabditis elegans reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that gld-4 activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with glp-1 mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of glp-1 mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.
Highlights
During development, tissues grow to form functional organs
A tight balance between selfrenewal and differentiation protects against tissue overgrowth or loss. This balance is strongly influenced by niche-mediated signaling pathways that primarily trigger a transcriptional response in stem cells to promote selfrenewal/proliferation
Post-transcriptional mRNA regulation emerged in diverse germline stem cell systems as an important gene expression mechanism, primarily preventing the protein synthesis of factors that promote the switch to differentiation
Summary
Animal tissues remain constant in size, in part, as a result of the dynamic balance between self-renewal/proliferation and differentiation. Perturbation of this balance affects tissue homeostasis and, compromises organ function. Tight regulatory mechanisms are in place to control the balance between self-renewal/proliferation and differentiation. One prevalent cell-extrinsic regulatory mechanism of stem cells to selfrenew/proliferate is their dependency on supporting niche cells, which trigger established signal transduction pathways that primarily lead to changes at the transcriptional level. To fine-tune proper tissue homeostasis and to provide tight feedback controls, additional cell-intrinsic gene expression mechanisms are likely to exist
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