Genetic studies of a pleiotropic transmembrane protease: insight from color variation in non-model organisms
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Principal Investigator: Gregory Stefan Barsh Organization: STANFORD UNIVERSITY Fiscal Year: 2024 Award: $665,448 Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases Project Summary/Abstract Mendelian variation in pigmentation is a rich genetic resource to identify and study signaling pathways relevant to human biology, but the repertoire of mutations that affect pigmentation in mice and in humans coat color has become saturated. Advances in genome sequencing technology now extend the reach of forward genetics beyond humans and model organisms to domestic and wild animals, for which there are many pigmentary phenotypes likely to represent conserved signaling pathways but whose molecular basis is unknown. Using pigmentary variation in domestic cats, our research group discovered a striking connection between a novel transmembrane protease encoded by Transmembrane aminopeptidase Q (Taqpep) and a secreted Wnt inhibitor encoded by Dickkopf 4 (Dkk4). Initial studies of Taqpep knockout mice reveal a role in multiple cell types and tissues including hair, the enteric nervous system, and the palate. In a different non-model organism, the plains zebra, Taqpep is a candidate gene for aberrant striping in an isolated population in Rwanda. Our results point to a central role for Taqpep in pathways and tissues that are directly relevant to human biology and disease, but a molecular understanding of those pathways is most effectively approached by combining forward genetics for gene discovery in non-model mammalian organisms with experimental genetics in laboratory mice and studies in cultured mammalian cells. We propose to: (1) Identify additional components of Taqpep action by forward genetics in Bengal cats and by analysis of fetal cat skin (2) Expand initial genetic studies of color pattern variation in zebras (3) Determine the mechanism of Taqpep action using experimental mouse genetics and proteomics Terms: <Acinonyx><Admixture><Affect><Aminopeptidase><Animals><Area><Asian><Biological Function><Biological Process><Black Panther><Body Tissues><Breeding><Candidate Disease Gene><Candidate Gene><Cats><Cats Mammals><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Characteristics><Cheetahs><Color><Communities><DNA><Darkness><Deoxyribonucleic Acid><Development><Domestic Animals><Domestic Cats><Enteric Nervous System><Esteroproteases><Exhibits><Experimental Genetics><Family Felidae><Felidae><Felids><Feline Species><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><GWA study><GWAS><Gene variant><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic study><Hair><Hair Color><Heritability><Human><Human Biology><Individual><Intracellular Communication and Signaling><Investigation><KO mice><Knock-out Mice><Knockout Mice><Laboratory Study><Laboratory mice><Leopard><Mammalia><Mammalian Cell><Mammals><Marble><Melanogenesis><Membrane><Mice><Mice Mammals><Modern Man><Molecular><Morphology><Murine><Mus><Mutant Strains Mice><Mutation><Names><Null Mouse><Organism><Palate><Panthera pardus><Panthera tigris><Pathway interactions><Pattern><Pedigree><Peptidases><Peptide Hydrolases><Phenotype><Pigmentation><Pigmentation physiologic function><Placenta Biology><Placental Biology><Placental Development><Placentation><Population><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Proteomics><Research><Role><Ruanda><Rwanda><Sampling><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Spottings><System><Technology><Testing><Tigers><Tissue Sample><Tissues><Variant><Variation><WNT Signaling Pathway><WNT signaling><Wild Animals><Work><Zebra><allele variant><allelic variant><biological signal transduction><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cell culture><cell cultures><cell type><developmental><discover genes><domesticated animal><entire genome><experiment><experimental research><experimental study><experiments><feline><fetal><forward genetics><full genome><gene discovery><gene interaction><genetic approach><genetic association><genetic pedigree><genetic resource><genetic strategy><genetic variant><genome mutation><genome sequencing><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><human disease><inhibitor><insight><living system><loss of function><membrane structure><model organism><mouse genetics><mouse mutant><name><named><naming><novel><pathway><pedigree structure><pigmentations><self organization><social role><trait><transcriptomics><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>