Here we show that the NgR family of proteins serves this important function. Our study suggests that NgRs function along the arbor of dendrites as a barrier that limits synapse formation. Loss of any one member of the NgR family is sufficient to reveal their inhibitory influence in vitro, whereas loss of all three NgRs is required

for abnormally elevated excitatory synaptogenesis in vivo. These findings broaden our understanding of NgR1′s function, since they identify a dendritic role for receptors whose function was hitherto ascribed mainly to the axon. At a mechanistic level, NgRs appear to work through the coordinated inhibition of synaptic and dendritic selleck growth. These findings are consistent with those of recent studies of more mature neuronal circuits, demonstrating that both Nogo and the Nogo receptor constrain dendritic growth (Zagrebelsky et al., 2010). The effects of NgR loss on synaptogenesis and dendrogenesis are coupled. Unlike Neuropilin-2, which has a more selective role in regulating the www.selleckchem.com/products/GDC-0449.html spatial distribution of synapses on a specific region of the dendrite, the primary apical shaft (Tran et al., 2009), the NgR family functions

broadly on the dendrite to restrict dendritic growth and limit the number of excitatory synapses that form. It will be important to identity the ligand or ligands that regulate the activity of the NgR family members in this developmental context. Several ligands have been shown to regulate NgR1 signaling. Recent work provides evidence that Nogo may promote synaptic maturation in more established neuronal circuits (Zagrebelsky et al., 2010 and Pradhan et al., 2010). Consistent with these findings, Sitaxentan we observe a significant increase in synapse density following Nogo-Fc (Nogo-66) addition to cultured hippocampal neurons (Z. Wills and M. Greenberg, unpublished observations), raising the possibility that Nogo may inhibit rather

than activate NgR in this context. These findings suggest that NgR1 signaling may fulfill multiple roles in synaptogenesis depending on its mechanism of activation and developmental period. Given that Nogo is highly enriched in the PSD (Peng et al., 2004 and Raiker et al., 2010), a better understanding of how ligand binding to NgR1 affects its downstream signaling may help to reveal how NgR1 regulates synapse number. It is noteworthy that of the known NgR1 ligands, only MAG can activate NgR2 (Venkatesh et al., 2005), and none have affinity for NgR3. These findings raise the possibility that NgR family members may bind different ligands, allowing each receptor to be tuned to distinct extracellular cues that function in parallel to inhibit synapse formation. Alternatively, these receptors may share a common ligand that remains to be be identified. NgR1 was originally discovered as a receptor that mediates the inhibition of axon regrowth after injury in the adult (Fournier et al., 2001).