The cis side of juxtacrine signaling: a new role in the development of the nervous system

Cell–cell communication by juxtacrine signaling plays a key role in the development of the nervous system, from cell fate determination through axonal guidance to synaptogenesis. Interestingly, several juxtacrine signaling systems exhibit an inhibitory interaction between receptors and ligands in the same cell, termed cis inhibition. These include the Notch, semaphorin and ephrin signaling systems. Here we review the role of cis inhibition in these signaling systems in the development of the nervous system. We compare and contrast cis inhibition mechanisms and discuss their potential cellular function as a threshold-generating mechanism. The prevalence of cis inhibition suggests that these interactions and their functional regulatory roles may serve as a general design principle for juxtacrine signaling-mediated processes during and beyond neurodevelopment.