PUBLICATION
Agrin/Lrp4 signal constrains MuSK-dependent neuromuscular synapse development in appendicular muscle
- Authors
- Walker, L.J., Roque, R.A., Navarro, M.F., Granato, M.
- ID
- ZDB-PUB-211030-10
- Date
- 2021
- Source
- Development (Cambridge, England) 148(21): (Journal)
- Registered Authors
- Granato, Michael
- Keywords
- Agrin, Appendicular, Lrp4, MuSK, Neuromuscular junction, Zebrafish
- MeSH Terms
-
- Agrin/metabolism*
- Animal Fins/innervation
- Animal Fins/metabolism
- Animals
- Axons/metabolism
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism*
- LDL-Receptor Related Proteins/genetics
- LDL-Receptor Related Proteins/metabolism*
- Muscle, Skeletal/innervation
- Muscle, Skeletal/metabolism*
- Mutation
- Neuromuscular Junction/metabolism*
- Receptors, Cholinergic/metabolism
- Signal Transduction
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 34714331 Full text @ Development
Citation
Walker, L.J., Roque, R.A., Navarro, M.F., Granato, M. (2021) Agrin/Lrp4 signal constrains MuSK-dependent neuromuscular synapse development in appendicular muscle. Development (Cambridge, England). 148(21):.
Abstract
The receptor tyrosine kinase MuSK, its co-receptor Lrp4 and the Agrin ligand constitute a signaling pathway that is crucial in axial muscle for neuromuscular synapse development, yet whether this pathway functions similarly in appendicular muscle is unclear. Here, using the larval zebrafish pectoral fin, equivalent to tetrapod forelimbs, we show that, similar to axial muscle, developing appendicular muscles form aneural acetylcholine receptor (AChR) clusters prior to innervation. As motor axons arrive, neural AChR clusters form, eventually leading to functional synapses in a MuSK-dependent manner. We find that loss of Agrin or Lrp4 function, which abolishes synaptic AChR clusters in axial muscle, results in enlarged presynaptic nerve regions and progressively expanding appendicular AChR clusters, mimicking the consequences of motoneuron ablation. Moreover, musk depletion in lrp4 mutants partially restores synaptic AChR patterning. Combined, our results provide compelling evidence that, in addition to the canonical pathway in which Agrin/Lrp4 stimulates MuSK activity, Agrin/Lrp4 signaling in appendicular muscle constrains MuSK-dependent neuromuscular synapse organization. Thus, we reveal a previously unappreciated role for Agrin/Lrp4 signaling, thereby highlighting distinct differences between axial and appendicular synapse development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping