The MuSK-BMP Pathway
Much of work in our laboratory is focused on the MuSK-BMP pathway. Originally discovered by Atilgan Yilmaz, a former graduate student in the lab, we found that MuSK is a BMP co-receptor shapes transcriptional output to BMP stimulation (Yilmaz et. al., 2016). Importantly, MuSK is only expressed in restricted set of cell types and thus it offers a precise avenue for manipulating BMP signaling in specific contexts (Fish & Fallon, 2020). We are pursuing this in vivo role in several contexts.
CNS
Muscle
The neuromuscular system in health, aging and ALS
Muscle stem cells (also known as satellite cells) are critical for maintaining muscle
strength and supporting regeneration. Satellite cells dysregulation is also thought to be a
key contributor to the loss of muscle function with aging (sarcopenia). Laura Madigan, a
former graduate student in the lab, discovered that the MuSK expressed in satellite cells is
important for maintaining their quiescence, and manipulation of the MuSK-BMP pathway
increases adult muscle size and strength.
Neuromuscular junction (NMJ) stability and function
The stability of the NMJ is essential for proper muscle function and it is compromised in a
range of diseases as well as in aging. Lauren Fish in the lab has shown that the MuSK-BMP
pathway is important for maintaining proper NMJ structure and function.
Promoting Adult Hippocampal Neurogenesis (AHN) in Alzheimer’s Disease and other
neurological disease
New neurons are both in the adult hippocampus throughout life. In the hippocampus these
adult-born neurons play a critical role in spatial learning as well as encoding emotion. Their
numbers and function are reduced in Alzheimer’s Disease, Parkinson’s Disease, Major
Depression and other neurological disorders (Babcock et. al., 2021). BMP signaling in
endogenous hippocampal neural stem cells regulates quiescence, activation and
neurogenesis. In collaboration with the Webb lab [link] we have discovered that the BMP
co-receptor MuSK is expressed in neural stem cells and regulates AHN. We are
investigating the mechanism by which MuSK functions in AHN. In collaboration with Bolden
Therapeutics, we are developing therapeutic agents targeting the MuSK-BMP pathway with
the goal of promoting AHN.
Regulation of myofiber size in slow muscle
Myofiber size is regulated by multiple intrinsic mechanisms including the Akt-mTOR
pathway. Diego Jaime, a former graduate student in the lab, has shown that the MuSK-
BMP pathway regulates Akt-mTOR signaling and myofiber size selectively in slow muscle (Jaime et. al., 2022).
