Project Grant K99GM151477

MAINTENANCE OF BRAIN HOMEOSTASIS BY AN ANCIENT ZINC METALLOCHAPERONE - SUMMARY ZINC BINDING METALLOPROTEINS AND METALLOENZYMES CONSTITUTE 10% OF THE VERTEBRATE METALLOPROTEOME AND ARE ESSENTIAL FOR MANY CELLULAR PROCESSES. DUE TO THE CRITICAL IMPORTANCE OF ZINC TO VERTEBRATE PHYSIOLOGY, ZINC DEFICIENCY LEADS TO NUMEROUS PATHOLOGIES AND IS INVOLVED IN THE PATHOGENESIS OF MANY NEUROLOGICAL DISORDERS. IN FACT, ZINC IS ONE OF THE MOST PREVALENT METAL IONS IN THE BRAIN WHERE IT SERVES IMPORTANT ROLES IN NEUROGENESIS, NEURONAL MIGRATION, AND DIFFERENTIATION. ZINC DEFICIENCY CONSTITUTES A PERVASIVE PUBLIC HEALTH PROBLEM CONSIDERING THAT APPROXIMATELY HALF OF THE WORLD'S POPULATION SUFFERS FROM DIETARY ZINC DEFICIENCY, NOW THE FIFTH MOST IMPORTANT RISK FACTOR FOR MORTALITY IN DEVELOPING COUNTRIES. DESPITE THE KNOWN IMPORTANCE OF ZINC COFACTORS TO CELLULAR FUNCTION, THE MECHANISMS BY WHICH ZINC LEVELS REGULATE TISSUE HOMEOSTASIS REMAINS POORLY DEFINED. CELLULAR ZINC HOMEOSTASIS IS MODULATED BY A SPECIALIZED FAMILY OF ZINC TRAFFICKING PROTEINS CALLED METALLOCHAPERONES. IT IS SPECULATED THAT METALLOCHAPERONES FACILITATE THE HIERARCHICAL DELIVERY OF METALS TO THEIR CLIENT PROTEINS THEREBY REGULATING CELLULAR AND ORGANISMAL HOMEOSTASIS. WE HAVE IDENTIFIED THE FIRST VERTEBRATE ZINC METALLOCHAPERONE, WHICH WE RECENTLY NAMED ZINC REGULATED GTPASE METALLOPROTEIN ACTIVATOR 1 (ZNG1). WE DEMONSTRATED THAT VERTEBRATE ZNG1 BINDS TO AND TRANSFERS ZINC TO METALLOPROTEINS TO PROMOTE THEIR ENZYMATIC ACTIVITY. FURTHER, WE IDENTIFIED NUMEROUS CANDIDATE ZNG1 CLIENT ZINC METALLOPROTEINS IN ZEBRAFISH AND MICE THAT ARE ASSOCIATED WITH BRAIN FUNCTION, INCLUDING THE ZINC-FINGER TRANSCRIPTION FACTORS, ZFHX3 AND ZFHX4. COLLECTIVELY THESE FINDINGS SUGGEST THAT ZNG1 IS A REGULATOR OF BRAIN DEVELOPMENT AND FUNCTION VIA INTERACTIONS WITH SPECIFIC ZN-REQUIRING TRANSCRIPTION FACTORS, WHICH WILL BE TESTED BY EXPERIMENTS PROPOSED IN THIS APPLICATION. THIS WORK IS EXPECTED TO DETERMINE THE IMPACT OF ZNG1 MEDIATED ZINC TRANSFER ON TRANSCRIPTION FACTOR ACTIVITY IN THE BRAIN (AIM 1) WHILE DEFINING THE ZNG1-DEPENDENT ZFHX3 AND ZFHX4 SIGNALING PATHWAYS IMPORTANT FOR NEURONAL DEVELOPMENT, NEURONAL RESPONSE TO STRESS, AND BEHAVIOR (AIM 2). COMPLETION OF THESE AIMS HAS THE POTENTIAL TO IDENTIFY ZNG1 AS A FACTOR THAT MODULATES SIGNALING IN THE BRAIN IN A MANNER THAT IS DEPENDENT UPON ZINC BIOAVAILABILITY. THESE FINDINGS WILL SHED LIGHT ON THE IN VIVO ROLE OF THE FIRST DISCOVERED ZINC METALLOCHAPERONE AND WILL VERTICALLY ADVANCE OUR UNDERSTANDING OF ZINC HOMEOSTASIS AND CONTRIBUTIONS TO THE PROGRESSION OF HUMAN NEUROLOGICAL DISORDERS.