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Principal Investigator: DUOJIA PAN
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $405,000
Funding agency: National Eye Institute
Project Summary / Abstract
My long-term scientific goal is to understand the molecular mechanisms that specify retina cell number. Using
the compound eye of Drosophila as an experimental model, my laboratory has discovered the Hippo pathway
as a central mechanism underlying this process. The core of the Hippo pathway comprises a kinase cascade
in which the Ste20 kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts).
Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus,
where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd). Our
research further established a critical role for the Hippo pathway in controlling organ size in mammals,
underscoring the importance of Drosophila as a powerful model to discover universal developmental
mechanisms.
Despite recent progress, our understanding of the composition, mechanism and regulation of Hippo signaling
remains incomplete. Much of our recent efforts have focused on discovering the missing components of the
Hippo pathway, with the ultimate goal of defining a complete Hippo signaling network. In the current grant
period, we have filled several key gaps in our understanding of the Hippo pathway, including a functional link
between Hippo signaling and the innate immunity receptor Toll, spectrin as an upstream regulator of Hippo
signaling by modulating actomyosin, autoinhibition of Hpo activity mediated by the STRIPAK phosphatase
complex, a Hpo-like kinase that functions redundantly with Hpo, a histone methyltransferase complex recruited
by Yki to activate the transcription of Hippo target genes, and a zinc finger transcriptional repressor recruited by
Sd to repress the transcription of Hippo target genes. We further contributed to the Hippo research community
by developing a set of fly stocks that can be used to unequivocally validate any Hippo pathway regulators through
rigorous genetic epistasis test.
In the next grant period, we will further elucidate the molecular underpinnings of the Hippo pathway through the
following specific aims. First, we will dissect the molecular and cellular mechanisms by which spectrin and
actomyosin cytoskeletons regulate Hippo signaling in developing tissues. Second, we will identify upstream
tumor suppressors that regulate Hippo signaling by antagonizing the activity of the STRIPAK phosphatase
complex. These studies will allow us to define how the STRIPAK phosphatase complex functions as a central
hub that integrates diverse upstream inputs into the Hippo pathway. Lastly, we will characterize novel regulators
of Hippo signaling isolated from a sensitized screen for mutations that enhance a partial loss-of-Hippo phenotype
in the eye. This unbiased approach will shed light on previously unforeseen regulators/mechanisms underlying
the Hippo pathway. Besides revealing fundamental mechanisms of eye development, the proposed studies will
have general implications for the development of other tissues.
Terms: <Actomyosin><Animals><Area><Atrophic><Atrophy><Basal Transcription Factor><Basal transcription factor genes><Biochemical><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Count><Cell Differentiation><Cell Differentiation process><Cell Nucleus><Cell Number><Cell Signaling><Cells><Cellular Matrix><Communities><Complex><Cytoskeletal System><Cytoskeleton><DNA Binding><DNA Binding Interaction><DNA bound><Dephosphorylation><Development><Developmental Biology><Drosophila><Drosophila eye><Drosophila genus><Epistasis><Epistatic Deviation><Exclusion><Experimental Models><Eye><Eye Development><Eyeball><Family><Fats><Fatty acid glycerol esters><Flies><Gene Down-Regulation><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Epistasis><Genetic Screening><Genetic Transcription><Genetic defect><Goals><Grant><Growth><Hyperplasia><Hyperplastic><Innate Immunity><Interaction Deviation><Intracellular Communication and Signaling><Kinases><Laboratories><Link><Malignant Cell><Mammalia><Mammals><Mediating><Merlin><Modeling><Moesin-Ezrin-Radixin-Like Protein><Molecular><Mutation><Myosin II><Myosin Type II><NF2><NF2 Gene Product><NF2 gene><Native Immunity><Natural Immunity><Neurofibromatosis 2 Gene Product><Neurofibromatosis 2 Genes><Neurofibromatosis Type 2 Protein><Neurofibromin 2><Non-Specific Immunity><Nonspecific Immunity><Nucleus><Oncogene Products><Oncogene Proteins><Oncoproteins><Organ><Organ Size><Pathway interactions><Phenotype><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Process><Protein Dephosphorylation><Protein Phosphorylation><Proteins><RNA Expression><Receptor Protein><Regulation><Research><Retina><Retinal Diseases><Retinal Disorder><Role><Schwannomerlin><Schwannomin><Schwannomin Protein><Signal Transduction><Signal Transduction Systems><Signaling><Specific qualifier value><Specified><Spectrin><Testing><Therapeutic Intervention><Tissue Growth><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Repression><Transcription Repressor><Transcription factor genes><Transcriptional Repression><Transcriptional Repressor><Transphosphorylases><Tumor Suppressor Proteins><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><biological signal transduction><cancer cell><cell transduction><cell type><cellular differentiation><cellular transduction><combinatorial><compound eye><developmental><epistatic relationship><eye morphogenesis><fly><fruit fly><gene repression><gene x gene interaction><genetic epistases><genetic repressor><genome mutation><histone H3 methyltransferase><histone methylase><histone methyltransferase><human disease><in vivo><insight><intervention therapy><intracellular skeleton><mutant><mutation scanning><mutation screening><nf 2 Genes><novel><ocular development><ontogeny><pathway><progenitor biology><progenitor cell biology><programs><receptor><recruit><retina disease><retina disorder><retinopathy><social role><stem and progenitor biology><stem cell biology><transcription factor><transduced cells><tumor suppressor>