title: Ttk69 acts as a master repressor of enteroendocrine cell specification in Drosophila intestinal stem cell lineages.
abstract: In adult Drosophila midgut, intestinal stem cells (ISCs) periodically produce progenitor cells that undergo a binary fate choice determined primarily by the levels of Notch activity that they receive, before terminally differentiating into enterocytes (ECs) or enteroendocrine (EE) cells. Here we identified Ttk69, a BTB domain-containing transcriptional repressor, as a master repressor of EE cell specification in the ISC lineages. Depletion of ttk69 in progenitor cells induced ISC proliferation and caused all committed progenitor cells to adopt EE fate, leading to the production of supernumerary EE cells in the intestinal epithelium. Conversely, forced expression of Ttk69 in progenitor cells was sufficient to prevent EE cell specification. The expression of Ttk69 was not regulated by Notch signaling, and forced activation of Notch, which is sufficient to induce EC specification of normal progenitor cells, failed to prevent EE cell specification of Ttk69-depleted progenitors. Loss of Ttk69 led to derepression of the acheate-scute complex (AS-C) genes scute and asense, which then induced prospero expression to promote EE cell specification. These studies suggest that Ttk69 functions in parallel with Notch signaling and acts as a master repressor of EE cell specification in Drosophila ISC lineages primarily by suppressing AS-C genes.
authors: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors: Chenhui
authors: C
authors: Wang
authors: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors: Xingting
authors: X
authors: Guo
authors: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors: Kun
authors: K
authors: Dou
authors: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors: Hongyan
authors: H
authors: Chen
authors: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China xirongwen@nibs.ac.cn.
authors: Rongwen
authors: R
authors: Xi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D019858:Enteroendocrine Cells / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D007422:Intestines / Q000166:cytology* / Q000196:embryology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; C407353:ase protein, Drosophila; C089197:sc protein, Drosophila; C075878:ttk protein, Drosophila
keywords: Drosophila midgut; Enteroendocrine cell; Intestinal stem cell; Notch; Prospero; Tramtrack; Ttk69; acheate-scute complex