The Conserved Misshapen-Warts-Yorkie Pathway Acts in Enteroblasts to Regulate Intestinal Stem Cells in Drosophila

• DOI: 10.1016/j.devcel.2014.09.012
• Publication Date: 2014-11-10T17:18:45Z
• Authors: Qi Li; Shuangxi Li; Sebastian Mana-Ca...; Rachel J. Roth Flach; Laura V. Danai; Alla Amcheslavsky; Yingchao Nie; Satoshi Kaneko; Xiaohao Yao; Xiaochu Chen; Jennifer L. Cotton; Junhao Mao; Dannel McCollum; Jin Jiang; Michael P. Czech; Lan Xu; Y. Tony Ip
• Keywords: 0303 health sciences; Stem Cells; Nuclear Proteins; Cell Differentiation; YAP-Signaling Proteins; Cell Biology; Protein Serine-Threonine Kinases; 03 medical and health sciences; Drosophila melanogaster; Trans-Activators; Animals; Drosophila Proteins; Regeneration; UMCCTS funding; Intestinal Mucosa; Protein Kinases; Cell Division; Developmental Biology; Signal Transduction

Similar to the mammalian intestine, the Drosophila adult midgut has resident stem cells that support growth and regeneration. How the niche regulates intestinal stem cell activity in both mammals and flies is not well understood. Here, we show that the conserved germinal center protein kinase Misshapen restricts intestinal stem cell division by repressing the expression of the JAK-STAT pathway ligand Upd3 in differentiating enteroblasts. Misshapen, a distant relative to the prototypic Warts activating kinase Hippo, interacts with and activates Warts to negatively regulate the activity of Yorkie and the expression of Upd3. The mammalian Misshapen homolog MAP4K4 similarly interacts with LATS (Warts homolog) and promotes inhibition of YAP (Yorkie homolog). Together, this work reveals that the Misshapen-Warts-Yorkie pathway acts in enteroblasts to control niche signaling to intestinal stem cells. These findings also provide a model in which to study requirements for MAP4K4-related kinases in MST1/2-independent regulation of LATS and YAP.