Regulation and function of interstitial axon branching in cortical projection neurons

Nervous system function is contingent on accurate neuronal connectivity patterns. A single neuron must often connect with multiple synaptic partners. Excitatory cortical projection neurons in the mammalian brain are a prime example of neurons whose axons innervate multiple distant target regions. This is made possible, in part, by interstitial axon branches that extend from axon shafts during development. The identification of molecular mechanisms that regulate interstitial axon branching in cortical projection neurons remains a major challenge. In this review, we summarize known stereotyped interstitial axon branching patterns in the mammalian brain and their spatiotemporal and molecular developmental cues. Taken together, these discoveries provide a foundation for understanding and identifying the molecular determinants that direct cortical connectivity during neural development.