Gli proteins constitute a vital but complex group of transcription factors. Humans have three, and mutations in them or errors in their regulation can cause developmental disorders or cancer. Our understanding of these proteins has rested on studies of their Drosophila ortholog Cubitus interruptus, which revealed that Gli proteins are a major target of the Hedgehog-??signaling pathway, and can be processed to produce either activators or repressors. However, key questions about Gli function remain unanswered. In particular, it is not clear how much of their activity is controlled by co-??factors, or what role they play in epigeneticchanges.SinceGliproteinsarebroadtranscriptionalregulators,thesequestionsarecritical. Caenorhabditis nematodes provide an ideal model for answering these questions. They have a single Gli protein,TRA-??1,thatsharesmanysimilaritieswithhumanGliproteins.However,TRA-??1controlssexualfates andplaysacentralroleinself-??fertility.Asaresult,thebalancebetweenitsactivatingandrepressingfunctions in the germ line makes C. briggsae ideal for identifying and evaluating co-??factors. Finally, the anatomy of C. briggsae and C. elegans are simple and completely defined, which makes it feasible to study tissue-??specific effectsofchromatinregulationduringdevelopment.Similarstudiesaredifficultinotheranimals. ThepowerofnematodegeneticsanddevelopmentalbiologywillsimplytheidentificationofGlico-??factors, and the analysis of how they work with TRA-??1 to activate or repress targets. Indeed, direct transcriptional controlandepigeneticeffectscanbothbestudiedinlivinganimals.Thus,thisproposalhasthreeaims:
Aim#3 :IdentifynewTRA-??1co-??factors. Since TRA-??1 is a model Gli protein, many of its co-??factors and regulatory interactions are likely to be conserved.Thus,identifyingco-??factorsandelucidatinghowtheyworkwithTRA-??1shouldilluminatehuman development and disease. In addition, novel co-??factors that are not shared with humans could define new targets for antihelminthic drugs. Since preventing adult worms from reproducing in their human hosts is a criticalformanagingparasiticnematodes,theabilitytotargetthispartofthesexdeterminationpathwaycould be invaluable. Finally, nematodes are one of the top models for sex determination (as shown by coverage in textbookslikeDevelopmentalBiology),soitiscriticalthatwedecipherthecentralpartofthestory.
GliproteinsbindtoDNAandturnmanyothergenesonoroff,solearninghowtheyworkand whytheysometimesmakemistakeswillhelpusunderstandmanycancersanddevelopmental disorders.BecauseGliproteinshavetointeractwithpartnerstowork,itiscrucialtoidentifyall ofthesepartnersandstudyeachoftheirroles.TheGliproteinTRA-??1,whichisfoundinsimple roundworms,providesanidealsubjectforansweringthesequestions.