Our results argue that natural selection acts predominantly on cell size and indirectly influences the spindle through the scaling of the spindle with cell size. Previous studies have shown that the spindle also scales with cell size during early development. Thus, the scaling of the spindle with cell size controls its variation over both ontogeny and phylogeny.

Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation also play roles in synapse maturation and homeostasis. In C. elegans the netrin receptor UNC-40/DCC controls the growth of dendritic-like muscle cell extensions towards motoneurons and is required to recruit type A GABA receptors (GABA A Rs) at inhibitory neuromuscular junctions. Here we show that activation of UNC-40 assembles an intracellular synaptic scaffold by physically interacting with FRM-3, a FERM protein orthologous to FARP1/2. FRM-3 then recruits LIN-2, the ortholog of CASK, that binds the synaptic adhesion molecule NLG-1/Neuroligin and physically connects GABA A Rs to prepositioned NLG-1 clusters. These processes are orchestrated by the synaptic organizer CePunctin/ MADD-4, which controls the localization of GABA A Rs by positioning NLG-1/neuroligin at synapses and regulates the synaptic content of GABA A Rs through the UNC-40-dependent intracellular scaffold. Since DCC is detected at GABA synapses in mammals, DCC might also tune inhibitory neurotransmission in the mammalian brain.