ARIANeuregulin

Prominent among these other mechanisms is neuregulin, or acetylcholine receptor inducing activity (ARIA). Neuregulin induces the expression of AChR genes and plays an important role in the patterning of postsynaptic gene expres-sion68. The neuregulin signal is transduced by ErbB receptors, of which ErbB2, ErbB3, and ErbB4 are present at the NMJ69-71. The function of neuregulin, however, is not in the early stages of synapse formation, but rather in maintaining the pattern of postsynaptic gene expression in the muscle following NMJ formation. This is supported by the phenotype of mice lacking isoforms of neuregulin containing the cysteine-rich domains, and by the simultaneous elimination of ErbB2 and ErbB4 in muscle72,73. In both cases, the early stages of NMJ formation are normal but motor-nerve terminals eventually degenerate. In both cases, the degeneration is consistent with a loss of Schwann cells, and not a primary defect in neuromuscular connectivity. These results demonstrate that synaptogenesis proceeds even with severely perturbed neuregulin signaling; they also highlight the importance of Schwann cells in NMJ maturation and maintenance.

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