Function of calcium exchangers in vetebrate pigmentation

Summary

Principal Investigator: KEITH CHI CHENG
Abstract: Cells containing melanin pigmentation aid vision, protect against UV radiation, and can transform into neoplasms. This proposal is based upon three related discoveries in our lab. 1) The zebrafish hypopigmentation mutant, golden, shows a melanosomal phenotype similar to that seen in light-skinned people. 2) The affected gene in this mutant is slc24a5, which encodes a putative K-dependent-Na/Ca exchanger. 3) A coding polymorphism in the human orthologue SLC24A5 is an important determinant of the difference in human skin color between Africans and Europeans. Our long-term goal is to elucidate the role and mechanism of the SLC24A5 protein in melanogenesis. We propose a collaborative, multidisciplinary approach that includes ultrastructural analysis, functional genomics, and transport studies. We are testing the hypothesis that slc24a5 is a calcium exchanger located in the membranes of melanosomes or their precursors, and that the organellar ionic milieu established by its transport activity is important in melanosome morphogenesis and pigment formation. Specific Aim 1 seeks to determine the subcellular distribution of the slc24a5 protein among melanosomes and their precursors using double-label, confocal immunofluorescence microscopy, subcellular fractionation, and immunoelectron microscopy. Specific Aim 2 combines ultrastructural analysis with antisense morpholino knockdown to define the morphogenetic roles of slc24a5. Specific Aim 3 seeks to establish the transport properties of the slc24a5 protein using a combination of calcium imaging, electrophysiology, and Ca-45 transport studies. Specific Aim 4 addresses the functional consequences of the common human polymorphism in SLC24A5. Findings from the proposed work will enhance our understanding of melanosome morphogenesis and melanin pigmentation in vertebrates, including humans. Melanin-containing cells aid vision, protect us from UV radiation, and when transformed, become one of the deadliest cancers in humans, malignant melanoma. This work will clarify how a newly-discovered sodium- calcium exchanger protein, first characterized in zebrafish, affects pigmentation, and lays a foundation for drugs to treat skin pigmentation problems, and perhaps malignant melanoma.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Skin color in fish and humans: impacts on science and society
    Keith C Cheng
    Department of Pathology, Penn State College of Medicine, Hershey, PA, USA
    Zebrafish 5:237-42. 2008
  2. pmc Skin color variation in Orang Asli tribes of Peninsular Malaysia
    Khai C Ang
    Department of Experimental Pathology and Jake Gittlen Cancer Research Foundation, Penn State College of Medicine, Hershey, Pennsylvania, United States of America
    PLoS ONE 7:e42752. 2012
  3. pmc Functional assessment of human coding mutations affecting skin pigmentation using zebrafish
    Zurab R Tsetskhladze
    Jake Gittlen Cancer Research Foundation, Penn State Hershey College of Medicine, Hershey, PA, USA
    PLoS ONE 7:e47398. 2012
  4. pmc Molecular phylogeography of a human autosomal skin color locus under natural selection
    Victor A Canfield
    Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania 17033
    G3 (Bethesda) 3:2059-67. 2013
  5. pmc Aquatic models, genomics and chemical risk management
    Keith C Cheng
    Jake Gittlen Cancer Research Foundation and Division of Experimental Pathology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA
    Comp Biochem Physiol C Toxicol Pharmacol 155:169-73. 2012
  6. pmc Whole-animal imaging, gene function, and the Zebrafish Phenome Project
    Keith C Cheng
    Jake Gittlen Cancer Research Foundation and Division of Experimental Pathology, Penn State Hershey College of Medicine, Hershey, PA 17033, United States
    Curr Opin Genet Dev 21:620-9. 2011

Scientific Experts

  • Keith C Cheng
  • Victor A Canfield
  • Khai C Ang
  • Steven M Wentzel
  • Stephen Oppenheimer
  • Arthur Berg
  • Katherine P Reid
  • Zurab R Tsetskhladze
  • Khai Chung Ang
  • Steven Peckins
  • Mei S Teh
  • Zamzuraida S Aida
  • Arthur S Berg
  • Badrul M Md-Zain
  • Hood Salleh
  • Mahani M Clyde
  • Danny Xr Koh
  • Mee S Ngu
  • Stephen L Johnson
  • Koichi Kawakami

Detail Information

Publications6

  1. pmc Skin color in fish and humans: impacts on science and society
    Keith C Cheng
    Department of Pathology, Penn State College of Medicine, Hershey, PA, USA
    Zebrafish 5:237-42. 2008
    ....
  2. pmc Skin color variation in Orang Asli tribes of Peninsular Malaysia
    Khai C Ang
    Department of Experimental Pathology and Jake Gittlen Cancer Research Foundation, Penn State College of Medicine, Hershey, Pennsylvania, United States of America
    PLoS ONE 7:e42752. 2012
    ..These results suggest that the Senoi are suitable for mapping East Asian skin color genes...
  3. pmc Functional assessment of human coding mutations affecting skin pigmentation using zebrafish
    Zurab R Tsetskhladze
    Jake Gittlen Cancer Research Foundation, Penn State Hershey College of Medicine, Hershey, PA, USA
    PLoS ONE 7:e47398. 2012
    ..The developed approach may be extended to other model systems and may potentially contribute to our understanding the functional relationships between DNA sequence variation, human biology, and disease...
  4. pmc Molecular phylogeography of a human autosomal skin color locus under natural selection
    Victor A Canfield
    Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania 17033
    G3 (Bethesda) 3:2059-67. 2013
    ....
  5. pmc Aquatic models, genomics and chemical risk management
    Keith C Cheng
    Jake Gittlen Cancer Research Foundation and Division of Experimental Pathology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA
    Comp Biochem Physiol C Toxicol Pharmacol 155:169-73. 2012
    ....
  6. pmc Whole-animal imaging, gene function, and the Zebrafish Phenome Project
    Keith C Cheng
    Jake Gittlen Cancer Research Foundation and Division of Experimental Pathology, Penn State Hershey College of Medicine, Hershey, PA 17033, United States
    Curr Opin Genet Dev 21:620-9. 2011
    ....