Genetic dissection of myelination in zebrafish [electronic resource]

Myelin is an evolutionary adaptation of the vertebrate nervous system that allows for the rapid propagation of action potentials along axons. Myelinated axons conduct electrical signals roughly 100 times faster than unmyelinated axons of the same caliber, allowing for a more compact and efficient nervous system. Defects in the formation, maintenance, or function of the myelin sheath underlie debilitating diseases, such as multiple sclerosis (MS), familial leukodystrophies, and peripheral neuropathies. Two types of glial cells make myelin in vertebrates: Schwann cells in the peripheral nervous system (PNS), and oligodendrocytes in the central nervous system (CNS). While these glial cells have been studied for years, much is still unknown: how are they specified from multipotent progenitors? What mechanisms direct glial cells to the appropriate axons and control the onset of myelination? How is myelin maintained in the adult, and how is it repaired after injury? How do myelinating glial cells control the development, and function of the associated neurons? In this dissertation, I take genetic approaches to identify new genes that are essential for the development and function of myelinating glia. Through a forward genetic screen for mutations that disrupt myelination in zebrafish, I discover several novel genes that play a role in CNS myelination. In particular, Chapter 3 details the study on a novel zinc finger protein (ZNF) Znf16l, which is essential for oligodendrocyte development. Mutations in this gene lead to a specific, transient delay in oligodendrocyte development and CNS myelination. I show that Znf16l functions autonomously in the oligodendrocyte lineage and that it regulates the progression between specification and migration of oligodendrocyte precursors. I also address the similarities and differences between loss of functions of Znf16l and Notch3, a previously described regulator of oligodendrocyte numbers and CNS myelination. Thorough analysis of the two mutations reveals the existence of genetically distinct populations of oligodendrocytes in zebrafish, similar to the ones described in mammals. In this dissertation, I also investigate the roles of Gpr126, a previously described regulator of PNS myelination. Recent controversial findings have described non-canonical roles of the N-terminal fragments (NTF) of Gpr126 independent of its well-established role in regulating the signaling activity of the C-terminal fragment (CTF). Using new mutant alleles I discovered in the genetic screen and others I constructed via genome editing, I address the incongruous findings and present evidence that the essential role of the NTF is to regulate the cAMP signaling activity of the CTF of Gpr126. Taken together, the work described in this dissertation identifies novel regulators of CNS myelination, analyzes one such regulator in depth, provides additional mutations that are being explored in other projects, and elucidates the activity of an essential regulator of PNS myelination.

Keywords: Developmental Biology.
Advisor: Talbot William
Barres Ben
Fuller Margaret
Kingsley David M. (David Mark) advisor. Thesis advisor