, 2002 and Haase et al., 2002). The transcriptional targets of Pea3 that control CM pool position remain to be defined, but several lines of evidence have implicated the selleck chemical activity of classical cadherins. The profile of classical type II cadherins in CM motor neurons is altered in Pea3 mutant mice ( Livet et al., 2002). Moreover, molecular and genetic experiments in chick and mouse have shown that classical cadherin signaling is required for the clustering and positioning of motor pools ( Price et al., 2002 and Demireva et al., 2011). Thus, as

Romanes surmised, the exposure of motor neurons to limb-derived signals is a key step in the positioning of some motor pools. The ability to disrupt normal programs of motor pool clustering and positioning through manipulation

of cadherin signaling has also permitted a test of Romanes’s second conjecture—that motor neuron positioning contributes to the precision and fidelity of muscle target innervation. Here, however, scrambling motor neuron position through inactivation of cadherin signaling fails to undermine the predictive link between the transcriptional identity of a motor neuron and the selection of its muscle target (Demireva et al., 2011). Presumably, profiles of expression and activity of Eph kinases and other relevant motor axonal guidance systems are established in a manner independent of motor neuron cell body position (Bonanomi and Pfaff, 2010). These findings argue against the idea that the clustering VX-770 supplier and settling position of motor neurons helps to assign patterns of muscle target connectivity. The clustering of motor neurons into pools may, nevertheless, still have relevance for the development of the neuromuscular system. At embryonic stages, motor neurons within a pool are connected by

gap junction channels, and active junctional communication has been argued to promote coherence in the firing of motor neurons that innervate a particular muscle target (Chang during et al., 1999). Clustering motor neurons into pools should therefore increase the probability that motor neurons with a common muscle target connect through gap junctions. In support of this view, analysis of mutant mice in which gap-junctional communication has been prevented by targeted inactivation of the connexin channel subunit Cx40 reveals that the coherence of motor neuron firing is decreased (Personius et al., 2007). In addition, fewer neuromuscular synapses are maintained at postnatal stages in these mutants—an indication that the durability of neuromuscular connections is compromised. Thus, one reason for clustering motor neurons into pools may be to promote the stability of synaptic connections with target muscles.