title: Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury.
abstract: Crypt epithelial survival and regeneration after injury require highly coordinated complex interplay between resident stem cells and diverse cell types. The function of Dclk1 expressing tuft cells regulating intestinal epithelial DNA damage response for cell survival/self-renewal after radiation-induced injury is unclear. Intestinal epithelial cells (IECs) were isolated and purified and utilized for experimental analysis. We found that small intestinal crypts of VillinCre;Dclk1f/fmice were hypoplastic and more apoptotic 24 h post-total body irradiation, a time when stem cell survival is p53-independent. Injury-induced ATM mediated DNA damage response, pro-survival genes, stem cell markers, and self-renewal ability for survival and restitution were reduced in the isolated intestinal epithelial cells. An even greater reduction in these signaling pathways was observed 3.5 days post-TBI, when peak crypt regeneration occurs. We found that interaction with Dclk1 is critical for ATM and COX2 activation in response to injury. We determined that Dclk1 expressing tuft cells regulate the whole intestinal epithelial cells following injury through paracrine mechanism. These findings suggest that intestinal tuft cells play an important role in regulating the ATM mediated DNA damage response, for epithelial cell survival/self-renewal via a Dclk1 dependent mechanism, and these processes are indispensable for restitution and function after severe radiation-induced injury.
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Chandrakesan
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weygant
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Qu
authors.affiliation: OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Berry
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Naushad
authors.initials: N
authors.lastname: Ali
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Chinthalapally
authors.initials: C
authors.lastname: Rao
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Huycke
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bronze
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.|COARE Biotechnology, Inc., Oklahoma City, OK 73104, USA.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage; D015232:Dinoprostone / Q000378:metabolism; D000089742:Doublecortin-Like Kinases; D020895:Enterocytes / Q000378:metabolism / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D011832:Radiation Injuries / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D016019:Survival Analysis; D014916:Whole-Body Irradiation
chemical_list: D015415:Biomarkers; D008840:Microfilament Proteins; C026615:villin; D051546:Cyclooxygenase 2; D000089742:Doublecortin-Like Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases; D015232:Dinoprostone