Myelin is a multi-lamellar sheath made from the plasma membrane of specialized glial cells that surrounds axons and allows for the rapid firing of action potentials in the nervous system. In addition to insulation, myelinating glia provide vitl trophic support and nutrients to axons and loss of myelin can result in severe diseases of the nervous system, including multiple sclerosis and Charcot-Marie-Tooth disease. Two unique myelinating glial cell types, oligodendrocytes (OLs) and Schwann cells (SCs), are responsible for myelination in the central nervous system (CNS) and peripheral nervous system (PNS), respectively. Although the implications of myelin loss or disruption for human health are clear, it is necessary to learn more about the development of myelinating glia in order to lay the foundation for developing new therapies for myelin diseases. To uncover new regulators of myelination, our lab performed a large-scale forward genetic screen in zebrafish. One of the mutants found in the screen, stl83, displayed a severe myelin reduction in both the CNS and PNS as well as axon swellings. Whole genome sequencing technology and complementation analysis were used to determine that the stl83 phenotype is the result of a missense mutation in the gene actin-related protein 10 (actr10), which encodes a critical component of the dynactin complex. Dynactin is necessary for proper function of the molecular motor dynein, which is responsible for the retrograde transport of cellular cargo, including organelles, mRNA, and proteins along microtubules. In general, actr10 is understudied; specifically, a role for actr10 in myelinating glia has never been described. This proposal therefore seeks to determine how actr10 regulates the development and myelination of OLs and SCs.
In Aim 1, I will characterize defects observed in actr10 zebrafish mutants in order to determine the stage at which actr10 regulates myelination and test whether the deficits are glial cell autonomous.
Aim 2 will investigate the mechanism whereby actr10 mediates myelination in glia. The proposed aims will illuminate how actr10 regulates myelination of the CNS and PNS.
Loss of the insulating myelin sheath essential for proper nervous system function underlies symptoms in devastating human conditions, including multiple sclerosis and Charcot-Marie-Tooth disease. However, basic development of the glial cells that produce myelin is incompletely understood, preventing production of effective therapies for diseases of myelin. By studying the actr10 gene, which we have shown causes myelin defects in both the central and peripheral nervous systems, we will gain a better understanding of the mechanisms by which glia myelinate.
|Cunningham, Rebecca L; Herbert, Amy L; Harty, Breanne L et al. (2018) Mutations in dock1 disrupt early Schwann cell development. Neural Dev 13:17|
|Herbert, Amy L; Fu, Meng-Meng; Drerup, Catherine M et al. (2017) Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo. Proc Natl Acad Sci U S A 114:E9153-E9162|
|Drerup, Catherine M; Herbert, Amy L; Monk, Kelly R et al. (2017) Regulation of mitochondria-dynactin interaction and mitochondrial retrograde transport in axons. Elife 6:|
|Herbert, Amy L; Monk, Kelly R (2017) Advances in myelinating glial cell development. Curr Opin Neurobiol 42:53-60|