MACF1 links Rapsyn to microtubule- and actin-binding proteins to maintain neuromuscular synapses

J Cell Biol. 2019 May 6;218(5):1686-1705. doi: 10.1083/jcb.201810023. Epub 2019 Mar 6.

Abstract

Complex mechanisms are required to form neuromuscular synapses, direct their subsequent maturation, and maintain the synapse throughout life. Transcriptional and post-translational pathways play important roles in synaptic differentiation and direct the accumulation of the neurotransmitter receptors, acetylcholine receptors (AChRs), to the postsynaptic membrane, ensuring for reliable synaptic transmission. Rapsyn, an intracellular peripheral membrane protein that binds AChRs, is essential for synaptic differentiation, but how Rapsyn acts is poorly understood. We screened for proteins that coisolate with AChRs in a Rapsyn-dependent manner and show that microtubule actin cross linking factor 1 (MACF1), a scaffolding protein with binding sites for microtubules (MT) and actin, is concentrated at neuromuscular synapses, where it binds Rapsyn and serves as a synaptic organizer for MT-associated proteins, EB1 and MAP1b, and the actin-associated protein, Vinculin. MACF1 plays an important role in maintaining synaptic differentiation and efficient synaptic transmission in mice, and variants in MACF1 are associated with congenital myasthenia in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adult
  • Animals
  • Child, Preschool
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Microfilament Proteins / physiology
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Mutation, Missense
  • Myasthenic Syndromes, Congenital / genetics
  • Myasthenic Syndromes, Congenital / metabolism
  • Myasthenic Syndromes, Congenital / pathology*
  • Neuromuscular Junction / physiology*
  • Pedigree
  • Receptors, Cholinergic / metabolism
  • Synapses / physiology*
  • Synaptic Transmission
  • Whole Exome Sequencing

Substances

  • Actins
  • MACF1 protein, human
  • Macf1 protein, mouse
  • Microfilament Proteins
  • Microtubule-Associated Proteins
  • Muscle Proteins
  • Receptors, Cholinergic
  • peripheral membrane protein 43K