Description
- Abstract:
- Muscle-specific tyrosine kinase (MuSK) is a transmembrane receptor tyrosine kinase first found at the post-synaptic domains of neuromuscular junctions (NMJs). It has long been known for its function in the formation and maintenance of NMJs through agrin-LRP4 signaling, which is dependent on the Ig1 domain of MuSK. Recently, the Fallon lab has shown that MuSK also shapes and augments BMP signaling through its binding to BMP and BMP co-receptors via the Ig3 domain. They termed this the MuSK-BMP pathway and generated a transgenic mouse model, ‘ΔIg3-MuSK’, which constitutively expresses MuSK lacking the Ig3 domain. With ΔIg3-MuSK as a tool, this work explores the functional roles of the MuSK-BMP pathway in various contexts, including the NMJ, where MuSK is enriched; the slow muscle, e.g., soleus, where MuSK is also known as expressed extrasynaptically; and the brain. Notably, MuSK expression is not well-characterized in the central nervous system. Here, we show that the density of voltage-gated sodium channel Nav1.4 reduced in ΔIg3-MuSK NMJs but not the sarcolemma, which explains the excitability defects previously found in ΔIg3-MuSK and indicates the role of the MuSK-BMP pathway in Nav1.4 localization at NMJs. Additionally, the level of type I collagen, a major component of extracellular matrix (ECM), was increased in the ΔIg3-MuSK soleus, suggesting the role of the MuSK-BMP pathway in fibrosis in the slow muscle. Finally, a panel of anti-MuSK antibodies for distinct domains and used for immunohistochemistry to localize MuSK protein in the brain. MuSK was detected in the subventricular zone (SVZ) of the lateral ventricle (LV) and the subgranular zone (SGZ) of the dentate gyrus, the two neurogenic niches in the brain. These data provide critical support for understanding the role of the MuSK-BMP pathway in regulating adult neurogenesis.
- Notes:
- Thesis (Sc. M.)--Brown University, 2024
Citation
Xi, Chengjie,
"Exploring functional roles of the MuSK-BMP pathway"
(2024).
Biotechnology, Biology and Medicine Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:swwjzgdw/
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Biology and Medicine Theses and Dissertations
Theses and Dissertations for the Biology and Medicine department....