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Cell fate determination: driven by a snowball rolling-like mechanism

Publication Date:2017/12/22

Caption: Phyllopod mediates a snowball-rolling mechanism to drive enteroendocrine cell differentiation from intestinal stem cells. This mechanism allows continuous and rapid accumulation of cell fate determinants that drive cell fate specification. (Image drawn by Mengli Shi)

December 21, 2017 - Rongwen Xi’s lab published online their newest research article in Stem Cell Reports entitled “A Phyllopod-Mediated Feedback Loop Promotes Intestinal Stem Cell Enteroendocrine Commitment in Drosophila”. In this article, the authors reported that Phyllopod (Phyl) mediates a positive feedback regulatory loop that drives enteroendocrine cell (EE) specification from intestinal stem cells (ISCs) in Drosophila.

The intestinal epithelium in the Drosophila midgut is maintained by ISCs, which are capable of generating both enterocyte (EC) and EE cells via alternative cell fate specification. Activation of Delta-Notch signaling directs ISCs for enterocyte generation, but how EEs are generated from ISCs remains poorly understood. Several years ago, Xi’s lab identified a transcriptional repressor,Ttk69, as a master repressor of EE fate specification from ISCs. Depletion of Ttk69 in ISCs causes uncontrolled generation of EEs, leading to the formation of enteroendocrine tumors in the intestinal epithelium. A regulatory axis downstream of Ttk69 composed of Achaete-Scute Complex (AS-C) and Pros transcription factors has been revealed. However, how Ttk69 itself is regulated is still unclear.

Post-translational modification of Ttk has been shown to promote R7 photoreceptor and sensory organ precursor (SOP) specification in Drosophila: the E3 ubiquitin ligase Sina and adaptor protein Phyl that ubiquitinate Ttk, which is subsequently degraded by proteasome. To investigate the potential function of sina and phyl in adult Drosophila midgut, the authors designed a series of genetic experiments and demonstrated that both sina and phyl are required for EE specification. ISCs could not differentiate into EEs when sina or phyl gene was depleted in ISCs, leading to EE-less intestinal epithelium. Conversely, overexpression of phyl is sufficient to induce ISC overproliferation and excessive generation of EEs, leading to the formation of enteroendocrine tumors. Further cellular, biochemical and genetic experiments demonstrate that Phyl functions as an adaptor protein to link Sina and Ttk69 for proteolytic degradation, and depletion of Ttk69 results in depression of AS-C genes. Interestingly, expression of AS-C genes further induces phyl expression, thereby establishing a positive feedback loop for continuous EE fate specification and commitment. Consistent with a role for Phyl in mediating this positive feedback loop, Phyl protein is specifically accumulated in differentiating EE progenitor cells.

In short, the authors identified a regulatory circuit composed of Sina-Phyl-Ttk69 and AS-C that drives EE commitment from ISCs. This mechanism allows rapid accumulation of important cell fate determinants, such as Pros in this case, to drive faithful cell fate commitment, and consequently, to maintain normal tissue homeostasis. Finally, the authors propose that this positive-feedback-circuit-engaged mechanism for faithful cell fate specification from committed progenitor cells could be a common strategy employed in diverse organisms, including mammals.

A Ph.D. student Chang Yin from the Rongwen Xi’s laboratory is the first author of this paper. Dr. Rongwen Xi is the corresponding author. The study was supported by grants from the Chinese Ministry of Science and Technology, and the municipal government of Beijing, and was conducted at the National Institute of Biological Sciences, Beijing.