Recent reports have identified a transcriptional network that specifies the embryonic stem cell fate, which facilitated the breakthrough development of reprogramming somatic cells into pluripotent stem cells. Furthermore, increasing evidences suggest that the identities of mature cells are also defined by transcriptional networks. However, the transcriptional networks that specify adult stem cell fates are largely uncharacterized, mainly because the transcription factors regulating somatic stem cell fates are unknown. In this study, we hypothesize that a transcriptional network specifies the intestinal stem cell (ISC) fate in Drosophila adult midgut (intestine). We propose to identify thes critical ISC transcriptional regulators to establish a comprehensive stem cell transcriptional network that governs the fly ISC fate. In our preliminary studies, taking advantage of a robust fly gut regeneration model, we performed an RNAi screen to identify transcription factors required for midgut regeneration. We have characterized several transcription factor hits, including da (E-protein), fkh (FoxA), klu and dSox9. Specifically, we showed that loss of these transcriptional factors in the midgut progenitors leads to their ectopic differentiation in the midgut. Furthermore our genetic and molecular studies indicate that fkh and da collaborate to induce downstream genes including dSox9 and klu to specify the ISC fate. Based on that, we hypothesize that these transcription factors likely function as an ISC transcriptional network, which we aim to elaborate in this study. First, we propose to determine how two critical ISC transcription factors Fkh and Da collaborate to maintain ISCs by identifying their downstream transcription factor targets. Second, we propose to establish an ISC transcriptional network that specifies the fly ISC cell fate. Third, we propose to explore the mechanism how niche signals regulate the ISC transcriptional network to promote the differentiation of midgut progenitors. The establishment of a comprehensive intestinal stem cell transcriptional network will facilitate the accurate identification of its downstream stem cell genes to allow for the unprecedented functional analysis in order to uncover potential novel stem cell functions.
This project uses the fruit fly gut as a simple system to study the mechanism of adult tissue homeostasis and regeneration. Specifically, we propose to genetically identify the transcriptional regulators that are required for maintaining the intestina stem cell fate to establish an intestinal stem cell transcriptional network.
|Lan, Qing; Cao, Min; Kollipara, Rahul K et al. (2018) FoxA transcription factor Fork head maintains the intestinal stem/progenitor cell identities in Drosophila. Dev Biol 433:324-343|
|Jiang, Huaqi; Tian, Aiguo; Jiang, Jin (2016) Intestinal stem cell response to injury: lessons from Drosophila. Cell Mol Life Sci 73:3337-49|