Netrin-1 is a secreted protein that directs long-range axon guidance during 
early stages of neural circuit formation and continues to be expressed in the 
mammalian forebrain during the postnatal period of peak synapse formation. Here 
we demonstrate a synaptogenic function of netrin-1 in rat and mouse cortical 
neurons and investigate the underlying mechanism. We report that netrin-1 and 
its receptor DCC are widely expressed by neurons in the developing mammalian 
cortex during synapse formation and are enriched at synapses in vivo. We detect 
DCC protein distributed along the axons and dendrites of cultured cortical 
neurons and provide evidence that newly translated netrin-1 is selectively 
transported to dendrites. Using gain and loss of function manipulations, we 
demonstrate that netrin-1 increases the number and strength of excitatory 
synapses made between developing cortical neurons. We show that netrin-1 
increases the complexity of axon and dendrite arbors, thereby increasing the 
probability of contact. At sites of contact, netrin-1 promotes adhesion, while 
locally enriching and reorganizing the underlying actin cytoskeleton through Src 
family kinase signaling and m-Tor-dependent protein translation to locally 
cluster presynaptic and postsynaptic proteins. Finally, we demonstrate using 
whole-cell patch-clamp electrophysiology that netrin-1 increases the frequency 
and amplitude of mEPSCs recorded from cortical pyramidal neurons. These findings 
identify netrin-1 as a synapse-enriched protein that promotes synaptogenesis 
between mammalian cortical neurons.