α-Dystroglycan is essential for the induction of Egr3, a transcription factor important in muscle spindle formation

Abstract

Muscle spindle fibers are specialized stretch receptors that allow the perception and coordination of limb movement. Differentiation of muscle spindles is initiated by signals derived from the in growing Ia sensory neurons during development. The sensory neuron secretes neuregulin which binds and signals through the ErbB receptors to initiate a signaling cascade. This cascade results in the expression of a specific repertoire of genes, one of which is the transcription factor Egr3, which is necessary in the development of muscle spindles. Signaling occurs efficiently when the postsynaptic receptors are clustered into large aggregates in apposition to an innervating nerve. Using what is known about acetylcholine receptor clustering at neuromuscular junctions as a model, this study shows the importance of the basal lamina proteins agrin and laminin and their shared receptor α-dystroglycan in aggregating ErbB receptors at sensory synapses. The study also shows that signaling through these receptors subsequently results in increased expression of Egr3, the transcription factor critical to muscle spindle fiber differentiation. Using an α-dystroglycan silenced culture, it is shown that α-dystroglycan is necessary to induce neuregulin, laminin and agrin induced Egr3. In these same myotube cultures there is also a reduced number of AChR-ErbB3 colocalized aggregates and this is not rescued with the addition of laminin. Taken together, these results suggest an essential role for basal lamina components and α-dystroglycan, molecules that are crucial in acetylcholine receptor aggregation at neuromuscular junctions, in the induction of the transcription factor Egr3, a critical transcription factor involved in muscle spindle fiber differentiation.