Department of Developmental Biology
Washington University School of Medicine
Dr. Monk studies the genetic and molecular mechanisms that govern the production of the myelin sheath. Using zebrafish genetics, she has identified essential receptors the regulate myelin formation. These studies will provide insight also into the mechanisms of demylenating disorders such as multiple sclerosis. Dr. Monk has published several high profile papers in centering on the discovery of an orphan G protein-coupled receptor (Gpr126) that is essential for myelination in zebrafish (Science, 2009) and mammals (Development, 2011). She obtained RO1 funding on her first submission in May, 2012 for the molecular and genetic analyses of Gpr126 in the peripheral nerve. She has continued her stellar career trajectory by recently obtaining a second RO1, also as the Principal Investigator. This work will focus on chemical and genetic screens to discover novel modulators of nervous system development.
BIRCWH Scholar from 01/01/2012 until 05/01/2012
Molecular mechanisms that govern the development of myelinated axons.
Myelin is a multilayered membrane that insulates and protects axons. Specialized glial cells,
oligodendrocytes and Schwann cells, generate myelin by spiraling their cell membrane and cytoplasm around axons. The myelin sheath that results from this process ensures that nerve impulses travel quickly and efficiently, ultimately allowing for the entire nervous system to function properly. Damage to or loss of this insulation can lead to debilitating symptoms in many diseases. In multiple sclerosis, oligodendrocyte myelin is attacked and destroyed by the body’s immune system. In peripheral neuropathies, myelin made by Schwann cells is lost or never formed. Peripheral neuropathies can be caused by diseases such as Guillan-Barre syndrome and Charcot-Marie-Tooth disease and are also a common complication of chemotherapy drug regiments. At present, our relative lack of understanding of the genetic and molecular mechanisms that govern the formation and homeostasis of myelin hinder the ability to design rational treatments for demyelinating diseases. To address these issues, we propose to further our understanding of the mechanisms by which oligodendrocytes and Schwann cells mature and form myelin during development. To this end, we will perform a large-scale genetic screen in zebrafish to find mutations that hamper the formation of myelinated axons. The fundamental properties of myelin are shared between zebrafish and humans, but zebrafish embryos are transparent and develop externally, allowing for exquisite visualization of many developmental processes, like glial cell development and myelination, which is not possible in mammals. The mutants with defective myelin that we find in our genetic screen will allow us to better understand how oligodendrocytes and Schwann cells develop, how they communicate with neurons, and how they ultimately make myelin. These studies will enhance our understanding of the basic biology of these critically important cells, and may point the way to novel therapeutics to promote regeneration in the nervous system.