Our goal is to understand the molecular and cellular mechanisms that coordinate to pattern complex epithelialorgans.Theseconservedmechanismsmustbecorrectlyregulatedtogeneratefunctionalorgansand are frequently re-utilized in mature organs to maintain homeostasis and function. We focus on a conserved familyofcoreadaptorproteinsthatarekeyregulatorsofcellandtissuestability:Cindr(inDrosophila)andthe mouseorthologsCin85andCd2ap.Cindrrecruitsproteincomplexesthatincludeactinregulatorsandsignaling proteins.Exploringthedynamicfunctionofthesecomplexes?andhowtheyareregulated-willelucidatethe system of molecular events that pattern tissues and how these go awry. In preliminary studies we observed functionalinteractionsbetweenCindrandtheDrosophilaJunterminalkinaseJNK(Bskinflies)andCindrand Mask(acomponentofHipposignaling)thatareessentialforcorrecttissuepatterning.Ourdatasupportsthe hypotheses that Cindr interacts with JNK/Bsk to restrict JNK (Specific Aim 1) and with Mask to promote its functionandthatofitscofactorYki(SpecificAim2)whichisrepressedwhenHipposignalingisactive.These preliminaryfindingshavefar-reachingimplicationsfirstlybecausethecontributionsofJNKandHipposignaling to organ morphogenesis are unclear. Second, the role of Cindr in regulating and integrating these signals during organ patterning has not been explored. To address these open questions, we will combine genetic, biochemical, immunofluorescence and live-cell-imaging approaches to elucidate the specific contributions of JNKandMaskandtheirinteractionswithCindrtoDrosophilaeyepatterning.
It is essential that organs are correctly shaped and patterned during development. Our research explores the molecular signals and cell behaviors that are coordinated to generate functional organs. Many of these mechanismsarealsousedlatertomaintainorganhomeostasisandfunctionandarereactivatedduringorgan repairorareco-optedtodrivedisease.Ourstudiesfocusonthefunctionofaconservedadaptorproteinfamily (Cindr/Cd2ap/Cin85)thatisessentialforepithelialorgandevelopmentandfunction.Aberrantfunctionofthese adaptorshasbeenimplicatedinmetastasis,Alzheimer?sDiseaseanddegenerativekidneydiseases.Together thesediseasesaccountforclosetothree-quarterofamilliondeathsintheUSeachyear.
| Bushnell, Henry L; Feiler, Christina E; Ketosugbo, Kwami F et al. (2018) JNK is antagonized to ensure the correct number of interommatidial cells pattern the Drosophila retina. Dev Biol 433:94-107 |
| Ketosugbo, Kwami F; Bushnell, Henry L; Johnson, Ruth I (2017) A screen for E3 ubiquitination ligases that genetically interact with the adaptor protein Cindr during Drosophila eye patterning. PLoS One 12:e0187571 |
