, 2005) and in regulating activity-dependent synaptic strengthening LY2835219 clinical trial in the hippocampus (Lee et al., 2008). However, robust expression of NgR family members begins in newborn mice (Lee et al., 2008), and its function at this stage of growth was unknown. Our study clarifies this issue by uncovering a role for the NgR family in the early postnatal

brain, where it functions in the dendrite to restrict synapse number. What might be the purpose of synaptic restriction by NgR family members? Our live-imaging studies suggest that the NgR family inhibits the formation of new synapses, possibly preventing premature synaptogenesis so that synapses are established at the correct time and place. In

addition, the NgR family may provide inhibition to counterbalance prosynaptic factors. Therefore, synapse formation might involve the concurrent activation of signaling pathways that promote synaptogenesis and a relief of inhibition of synapse formation by the NgR family. Consistent with these possibilities, we provide evidence this website that NgR1 mediates its effects through the activation of RhoA, a GTPase that restricts actin polymerization and thereby limits dendritic growth and spine development (Elia et al., 2006 and Sin et al., 2002). Signaling through RhoA to regulate actin assembly may be a common feature of NgR signaling. Previous work has shown that NgR1 regulates actin dynamics in the axon through TROY, RhoA, and ROCK (Yiu and He, 2006). In the present study, we provide evidence that a similar signaling pathway mediates the effects of NgR1 in the dendrite. While we have found that TROY can

bind both NgR1 and NgR2 in heterologous cells (Figures S4E and S4F), future work will be required to demonstrate Mephenoxalone the presence of a protein complex comprised of these signaling components in developing dendrites. Further, the signals promoting synaptic and dendritic growth may not be identical. Preliminary work suggests that while TROY inhibits synapse development, it does not inhibit dendritic growth (Wills and Greenberg, unpublished data). However, the finding that NgR1 regulates both dendritic and synaptic growth suggests that NgR1 signaling may couple these processes to coordinate neuronal development. Though our studies were focused on elucidating the developmental function of the NgRs, expression of this family of proteins continues into adulthood, and so it is interesting to speculate that NgR may continue to limit dendritic growth and synapse number in the mature brain. If so, NgR1′s dendritic function may be important to consider in the context of neural damage caused by, e.g., injury or stroke, where, it has been suggested, NgR1-mediated inhibition of axonal outgrowth impairs recovery of motor function (Lee et al., 2004 and Harvey et al., 2009).