Retrograde regulation of motoneuron differentiation by muscle β-catenin

Abstract

Synapse formation requires proper interaction between pre- and postsynaptic cells. In anterograde signaling, neurons release factors to guide postsynaptic differentiation. However, less is known about how postsynaptic targets retrogradely regulate presynaptic differentiation or function. We found that muscle-specific conditional knockout of beta-catenin (Ctnnb1, also known as beta-cat) in mice caused both morphologic and functional defects in motoneuron terminals of neuromuscular junctions (NMJs). In the absence of muscle beta-catenin, acetylcholine receptor clusters were increased in size and distributed throughout a wider region. Primary nerve branches were mislocated, whereas secondary or intramuscular nerve branches were elongated and reduced in number. Both spontaneous and evoked neurotransmitter release was reduced at the mutant NMJs. Furthermore, short-term plasticity and calcium sensitivity of neurotransmitter release were compromised in beta-catenin-deficient muscle. In contrast, the NMJ was normal in morphology and function in motoneuron-specific beta-catenin-deficient mice. Taken together, these observations indicate a role for muscle beta-catenin in presynaptic differentiation and function, identifying a previously unknown retrograde signaling in the synapse formation and synaptic plasticity.

Wnt/β-Catenin Signaling Suppresses Rapsyn Expression and Inhibits Acetylcholine Receptor Clustering at the Neuromuscular Junction

“…5F), both of which are believed to inhibit AChR clustering (37,52). In contrast to the effect of ␤-catenin in cultured muscle cells, a recent report shows that muscle-specific deletion of the ␤-catenin gene resulted in an increase in the size of AChR clusters, probably due to the retrograde effect of muscle ␤-catenin on presynaptic transmitter release (53). It is known that ACh acts to disperse AChR clusters (4,5,8).…”

Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

“…In support of the idea that agrin induces the release of a retrograde signal capable of disinhibiting presynaptic specialization, we found that agrin induces FGF expression in muscle and conversely, that muscle from agrin-deficient mice expresses less FGF than muscle from control mice. However, other retrograde factors such as β-catenin are required for antagonizing AChinduced inhibition of presynaptic differentiation such as β-catenindependent signals (51).…”

Modulation of Agrin-induced Acetylcholine Receptor Clustering by Extracellular Signal-regulated Kinases 1 and 2 in Cultured Myotubes

“…Presynaptic defects are supposedly due to lack of proper agrin-induced retrograde signaling from muscle to nerve that accounts for the maturation of the growth cone into a nerve terminal. The intracellular pathways that mediate this signaling are unknown, however, it seems that ␤-catenin is a key player (41). It is tempting to suggest that agrin-induced ERK1/2 activation might be part of a retrograde signaling pathway that regulates pre-synaptic differentiation.…”