Here we seek to understand how translational control of mRNAs within adult stem cells controls their ability to divide symmetrically. This area of study is significant because such symmetric renewal is a fundamental but poorly understood behavior of stem cells that is responsible for tissue growth, remodeling and regeneration in animals including humans. Addressing this deficit, we have found that the RNA-binding protein LIN-28 is specifically expressed in adult intestinal stem cells (ISCs) of the Drosophila model organism and is required for the expansion of this stem cell population during growth of the intestinal epithelium in response to food consumption. Since vertebrate LIN-28 is also known to promote regeneration, the goal of this grant is to use the unique advantages of the genetically tractable Drosophila model to rigorously delineate the conserved mechanistic activity, relevant substrates, and required cofactors that LIN-28 normally uses to promote the symmetric renewal of stem cells. We propose to accomplish this goal by focusing our experiments on a specific hypothesis that is based on our functional analysis of LIN-28 in ISCs as well as large scale proteomic and transcriptomic analyses we conducted that identified putative LIN-28 binding partners and mRNA targets in ISCs. Our hypothesis is that a stem cell specific ribonucleoprotein (RNP) complex, including LIN-28, boosts translation of target mRNAs during nutrient- deprived conditions in order to poise stem cells to divide symmetrically when nutrients become available. To accomplish our goal, we propose the following three overlapping areas of investigation: 1) Test whether adaptive growth is controlled by the ratio between LIN-28 and a second RNA-binding protein called FMR1 in ISCs; 2) Determine how LIN28 and FMR1 regulate mRNA targets during adaptive tissue resizing; 3) Investigate whether LIN28 and FMR1 function by excluding one another from a larger mRNP complex. We expect that these proposed studies will delineate a novel, conserved pathway that controls symmetric self- renewal of stem cells in response to environmental cues. Medical interventions that trigger this pathway could be used to promote the regenerative process and therefore would have wide applicability in treating aging-related and congenital disorders.
Stem cell expansion underlies tissue development and regeneration and, when uncontrolled, causes human disease, including cancer. This project addresses several aspects of how mRNA translation within stem cells controls this expansion, including the identities and functions of responsible proteins as well as the identities of their relevant mRNA targets. By illuminating the mechanisms of this process, this work should lead toward medical interventions that would have wide applicability in treating aging-related and congenital disorders.
|Luhur, Arthur; Buddika, Kasun; Ariyapala, Ishara Surangi et al. (2017) Opposing Post-transcriptional Control of InR by FMRP and LIN-28 Adjusts Stem Cell-Based Tissue Growth. Cell Rep 21:2671-2677|