My graduate and postdoctoral training has impressed upon me the importance of understanding the molecular mechanisms of basic cell biological processes and their contribution to pathologies underlying humandisease.AsIpreparetotransitionintoanindependentresearchposition,Imcompelledtoacquirethe additional technical skills and education that will enable me to gain research autonomy and develop an innovativebasicresearchprogramaddressingfundamentalquestionsincellanddevelopmentalbiology.Asa postdoctoralfellowwithElaineFuchsatTheRockefellerUniversity,Ifindmyselfinanidealenvironmentthat will foster my continual growth as a scientist and mentor, and enable me to acquire additional technical expertiseandgenerateresearchmaterialsthatwillfacilitatemyfutureindependentresearchendeavors. One fundamental question in developmental biology is how an individual cell may sense its environment to transmit extracellular signals that control cell signaling and proliferation during tissue morphogenesis. This activation of developmental cell signaling pathways must be temporally and spatially regulated in order to balance tissue growth with differentiation. When this goes awry during normal tissue homeostasis,proliferativeconditionssuchaspolycystickidneydisease(PKD)andcancerarise.Thelongterm objective of my proposal is to understand how primary cilia temporally and spatially regulate developmental signaling and cell proliferation during epidermal morphogenesis. The primary cilium is a microtubulebased cellularantennathatcansensetheextracellularenvironment,transmitdevelopmentalsignals,andinfluence cellcycleprogression.Dysfunctionalciliaresultinhumangeneticdiseasesreferredtoasciliopathies,andin diseasesthatprecipitatethetransitionfromcellularquiescencetoproliferation,suchasPKDandcancer. Preliminary data indicate that primary cilia play at least two temporally and spatially distinct roles in balancing growth and differentiation during skin development: a novel, early role in epidermis, whose morphogenesisreliesuponNotchsignaling?andalaterroleinhairfollicles,reliantuponSonicHedgehog(Shh) signaling. Although the reliance of Shh signaling on cilia is expected and wellcharacterized in other model systems,themolecularmechanismsunderlyingciliamediatedcontrolofNotchsignalingandcellproliferation during epidermal morphogenesis are unknown. I hypothesize that spatial and temporal activation of Notch signalingandepidermalproliferationaredirectlyregulatedbyprimaryciliaduringnormalskindevelopment.To testthiscentralhypothesisIwill1)Characterizethespatialandtemporallocalizationanddynamicsofnotch signalingcomponentsattheprimaryciliaduringcelldivisionanddifferentiation.2)Determineifknownciliary traffickingmechanismsregulatethelocalization,activation,andfunctionofNotchsignalingcomponentsduring epidermal differentiation. 3) Identify the cellcycle regulatory factors that function in ciliamediated control of epidermalproliferationduringskindifferentiationandhairfolliclemorphogenesis.
Theprimaryciliumisacellularantennathatcansensetheextracellularenvironment,transmitdevelopmental signals,andinfluencecellcycleprogression.Nonfunctionalciliacontributetoproliferativediseasessuchas polycystickidneydiseaseandcancer,andcauseaspectrumofgeneticdiseasescalledciliopathies,which affectnumerousorgansystemsandtissues.Thediversityoforgansystemsaffectedinthesehumangenetic diseaseshighlightthenecessitytodeveloptissuespecificmodelsystems,suchastheskin,tostudythe functionofprimaryciliaduringdifferentiation,tissuemorphogenesis,cellproliferationandcancer.
| Ezratty, Ellen J; Pasolli, H Amalia; Fuchs, Elaine (2016) A Presenilin-2-ARF4 trafficking axis modulates Notch signaling during epidermal differentiation. J Cell Biol 214:89-101 |
