MOTOR EXIT POINT GLIA

Recent studies from the lab show that MEP glia myelinate spinal motor root axons in a discrete region located between oligodendrocytes, which myelinate spinal cord axons, and Schwann cells, which myelinate motor nerves. Currently, we are elucidating how MEP glia interact with Schwann cells to myelinate distinct, non-overlapping peripheral axonal segments and the mechanisms that mediate these interactions. We are also investigating if we can divert MEP glia from spinal motor roots and take advantage of their myelinating property along more proximal locations of motor nerves in Schwann cell deficient zebrafish models. Finally, we previously showed that MEP glia express a range of markers including a combination of both CNS and PNS glial markers as well as one boundary cap cell marker. We are now interested in understanding the role of the latter in MEP glial development and function.

OPC HOMEOSTASIS

Oligodendrocytes myelinate central nervous system (CNS) axons in order to facilitate conduction of electrical impulses and provide protection from the surrounding environment. They are derived from oligodendrocyte progenitor cells (OPCs), which migrate throughout the developing CNS and become evenly distributed. While most OPCs mature into oligodendrocytes, a population of OPCs remains evenly distributed in the CNS throughout adulthood. In both developing and mature nervous systems, OPCs are highly motile cells with dynamic membrane processes that change direction and retract their processes upon contact with neighboring OPCs. This phenomenon, known as contact-mediated repulsion (CMR), influences the local migratory behavior of OPCs. However, how CMR between OPCs is molecularly controlled and how CMR influences the global distribution of OPCs within the CNS, are unknown.  This project will determine the molecular mediators of CMR between OPCs and how CMR influences the overall patterning of OPCs in the CNS.

PERINEURIAL GLIAL DEVELOPMENT

Previous studies from the lab show that during nervous system development, perineurial glia migrate out of the spinal cord through motor exit points (MEP) and ensheath motor axon-Schwann cell complexes, ultimately differentiating into the perineurium, a component of the blood-nerve-barrier. However, how perineurial glia are specified in the spinal cord and migrate through MEPs are still unknown. Our goal is to understand the early development of perineurial glia and identify the molecular mechanisms behind their migration through the CNS-PNS transition zone.

---

GLIAL DIVERSITY

The peripheral nervous system (PNS) contains different types of glia with diverse functions such as myelinating peripheral axons, forming the perineurium and maintaining the boundary between the peripheral and central nervous system. These glial types arise from different locations, have different developmental behaviors, acquire different morphologies and express unique combinations of genes. Although we are beginning to understand how peripheral glia develop and know a few of the genes important for their function, the full molecular programs that regulate their specification, migration, differentiation and function are unknown. Furthermore, there is increasing evidence that there is a far greater amount of glial diversity in the PNS than previously appreciated. In order to determine the level of glial heterogeneity in the PNS, we are interrogating the transcriptomes of several PNS glial subtypes. These studies will not only help us understand more about how peripheral glia develop, but will also help us investigate the distinct roles and molecular changes that occur in specific glial populations following nerve injury and demyelinating diseases.

OPC AND MEP GLIA CHARACTERIZATION

The central and peripheral nervous systems, often thought of as distinct halves, physically interact at transition zones (TZ). In these areas, axons cross from the spinal cord into the periphery or vice versa. Oligodendrocytes within the spinal cord migrate along axons and even contact peripheral glia at the TZ, but somehow a boundary is formed that prevents the oligodendrocytes from migrating onto the peripheral nerve itself. Our lab discovered motor exit point (MEP) glia, which are responsible for preventing peripheral oligodendrocyte migration. However, how MEP glia signal to and repel oligodendrocytes is not known. We have performed a screen of small molecule inhibitors to identify candidate signals that restrict oligodendrocyte migration at the TZ. The goal is to understand the developmental program that establishes distinct domains for central and peripheral glia. This also raises the possibility that oligodendrocytes could be recruited to the peripheral nervous system in patients with diseases of peripheral myelin, such as Charcot-Marie-Tooth. 

---

DEMYELINATION MODEL

Perineurial glia are the cells that form the blood-nerve-barrier. We are inerested in investigating the plasticity of these cells in response to myelin perturbations. Furthermore, we are characterizing a novel focal demyelination model in zebrafish that will allow for the visualization of demyelination and remyelination ​in vivo.

PERINEURIAL GLIA RESPONSE TO INJURY

Previous studies in the lab implicated perineurial glia as essential mediators of spinal motor nerve degeneration and subsequent regeneration. After nerve injury, perineurial cells not only phagocytize debris, but also bridge the injury gap prior to axon regrowth. While we now know that it is this glial bridge that is essential for regeneration, the cellular and molecular mechanisms that underlie this process are poorly understood. We are now interested in identifying the molecular mechanisms that mediate this essential perineurial glia migration following injury.

---

---

A MODEL OF DMD

A forward genetic screen conducted in the lab led to the identification a mutant with severe neural patterning defects. Whole Genome Sequencing and complementation testing identified this mutant as a novel allele of dystrophin. Dystrophin mutations are infamously known to be the cause of the debilitating disease, Duchenne Muscular Dystrophy. Loss of dystrophin most drastically affects muscle function, and children with the disease are often wheelchair bound by the age of 10.  Most studies of the disease focus on the muscular phenotypes, but we intend to use this novel zebrafish model to investigate a neurogenic component to this disease. This study has the potential to revolutionize and contribute to current efforts to cure DMD.