Project Grant R01NS134768

MECHANISMS OF CNS MYELIN TARGETING - PROJECT ABSTRACT: EFFICIENT VERTEBRATE NERVOUS SYSTEMS REQUIRE THE PRECISE INSULATION OF CENTRAL NERVOUS SYSTEM (CNS) AXONS BY MYELINATING OLIGODENDROCYTES. HOWEVER, WE KNOW VERY LITTLE ABOUT HOW AXONS ARE SELECTED FOR MYELINATION AND WHY SOME CNS STRUCTURES ARE AVOIDED. WE SET OUT TO INVESTIGATE THESE QUESTIONS AND IDENTIFIED SEVERAL GENES, INCLUDING JUNCTION ADHESION MOLECULES 2 & 3 (JAMS 2 & 3) AND TRANSMEMBRANE PROTEIN 125B (TMEM125B) AS PUTATIVE REGULATORS OF CNS MYELIN TARGETING AND GROWTH. TMEM125B IS EXPRESSED IN MATURE, MYELINATING OLIGODENDROCYTES IN ZEBRAFISH, MICE, AND HUMANS WITH AN EXPRESSION PATTERN THAT IS CONSISTENT WITH ITS POSSIBLE ROLE IN MYELIN TARGETING AND MYELIN MAINTENANCE AND JAMS 2 & 3 ARE EXPRESSED IN NEURONS AND OLIGODENDROCYTE LINEAGE CELLS. IN OUR PRELIMINARY STUDIES, WE HAVE DISCOVERED THAT MUTATIONS OF TMEM125B AS WELL AS JAMS 2 & 3 CAUSE ECTOPIC MYELINATION OF CNS NEURONAL SOMA, CONSISTENT WITH A ROLE FOR THESE PROTEINS IN MYELIN TARGETING AND/OR GROWTH. IN THIS APPLICATION, WE WILL EXTEND THESE FINDINGS TO: 1) DETERMINE THE ROLE OF TMEM125B IN CNS MYELINATION (AIM 1), 2) CHARACTERIZE THE ROLE OF JAMS 2 & 3 IN DEVELOPMENTAL MYELINATION (AIM 2), AND 3) IDENTIFY THE BINDING PARTNERS FOR TMEM125B THAT INHIBIT ECTOPIC MYELINATION TO NEURONAL SOMA (AIM 3). WHEN COMPLETE, WE WILL HAVE A DEEPER UNDERSTANDING OF THE ROLE OF TMEM125B AND JAMS 2 & 3 IN CNS MYELINATION AS WELL AS INSIGHT INTO THE MECHANISMS THAT DRIVE APPROPRIATE MYELIN TARGETING DURING DEVELOPMENT.