Abstract
The heparan sulfate proteoglycan agrin is best known for its essential role during formation, maintenance and regeneration of the neuromuscular junction. Mutations in agrin-interacting proteins are the genetic basis for a number of neuromuscular disorders. However, agrin is widely expressed in many tissues including neurons and glial cells of the brain, where its precise function is much less understood. Fewer synapses develop in brains that lack agrin, consistent with a function of agrin during CNS synaptogenesis. Recently, a specific transmembrane form of agrin (TM-agrin) was identified that is concentrated at that interneuronal synapses in the brain. Clustering or overexpression of TM-agrin leads to the formation of filopodia-like processes, which might be precursors for CNS synapses. Agrin is subject to defined and activity-dependent proteolytic cleavage by neurotrypsin at synapses and dysregulation of agrin processing might contribute to the development of mental retardation. This review summarizes what is known about the role of agrin during synapse formation at the neuromuscular junction and in the developing CNS and will discuss additional functions of agrin in the adult CNS, in particular during BBB formation, during recovery after traumatic brain injury and in the etiology of diseases, including Alzheimer‘s disease and mental retardation.
Financial & competing interests disclosure
The work in our laboratory is supported by the Deutsche Forschungsgemeinschaft (Kr 1939/7) and by grants from the German Society for Muscle Disease and the Friedrich Baur Stiftung. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Acknowledgements
The authors thank John L Bixby for careful reading and improvement of the manuscript and for many insightful comments.