In the vertebrate peripheral nervous system, Schwann cells (SCs) make myelin that insulates large axons and allows rapid conduction of nerve impulses. Myelinating SCs possess the innate ability to demyelinate and transform into repair SCs, which promote axonal regeneration and remyelination after traumatic injury. Demyelination can also occur pathologically, and there are no effective treatments to promote or enhance remyelination after injury or disease. Myelination during development is triggered by activation of several SC membrane-associated proteins, and requires that the transcription factor Krox20 be in the nucleus. However, we know little about how myelination signals move from the membrane to the nucleus during development and even less about the signaling required for myelin maintenance and remyelination. YAP/TAZ are paralogous transcriptional co-activator proteins with diverse cellular functions, known best as potent promoters of cell proliferation. Their activity is regulated by nucleocytoplasmic shuttling: when nuclear, they are transcriptionally active. We recently showed that in SCs, YAP/TAZ are nuclear and required for Krox20 expression, myelin formation and maintenance, suggesting that YAP/TAZ shuttle signals from membrane to nucleus to regulate myelination. These findings lead us to hypothesize that YAP/TAZ are a nexus for multiple signaling pathways that lead to transcriptional activation of Krox20 and myelin genes, and which thereby regulate developmental myelination, myelin maintenance, demyelination and remyelination. To test our hypothesis, we propose the following Aims: 1) Determine if YAP/TAZ mediate demyelination and remyelination; 2) Identify upstream regulators of YAP/TAZ in myelin formation and maintenance; 3) Determine how YAP/TAZ regulate transcription of Krox20 and myelin genes. We will use unique and conventional in vitro and in vivo techniques, including multiple lines of inducible transgenic mice and RiboTag translatome profiling. The proposed study should significantly enhance our understanding of how SCs form, maintain and repair peripheral myelin. It is also likely to provide important new insights into how to prevent demyelination or promote robust remyelination in peripheral nerve diseases.
Damage of the myelin sheath that insulates our nerves produces devastating loss of motor and sensory function. Its causes include traumatic injury, demyelinating neuropathies, inflammation, chemotherapy, autoimmune disease and diabetes, which affect many millions of Americans. The proposed study will provide new insights into how we can prevent demyelination and promote robust remyelination in patients with demyelinating disorders.
