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Mentions: Cortical axons navigate over long distances by responses of their motile growth cones to attractive and inhibitory guidance cues in their environment. However, the growth cone at the tip of the primary axon does not typically grow directly into cortical and spinal targets. Instead branches arise interstitially from the axon shaft and then enter targets where they then form terminal arbors. Axon branching may be mechanistically linked to pausing behaviors of growth cones, which leave behind remnants on the axon at sites of future branching (Kalil et al., 2000; Dent et al., 2003). Growth cones consist of a central region which contains bundled microtubules and a thin expanded peripheral region dominated by actin filaments that form a meshwork in veil-like lamellipodia and bundles in fingerlike filopodia that protrude from highly motile lamellipodia (Figure 1). The growth cone responds to attractive cues by turning toward the source of the positive guidance cue whereas inhibitory guidance cues repel axons away from the repulsive guidance cue (Huber et al., 2003).
Signaling Mechanisms in Cortical Axon Growth, Guidance, and Branching
Bottom Line: A major challenge is to relate findings in tissue culture to mechanisms of cortical development in vivo.Toward this goal, we describe our recent work in cortical slices, which preserve the complex cellular and molecular environment of the mammalian brain but allow direct visualization of growth cone behaviors and calcium signaling.Findings from this work suggest that mechanisms regulating axon growth and guidance in dissociated culture neurons also underlie development of cortical connectivity in vivo.
Affiliation: Neuroscience Training Program, University of Wisconsin-Madison Madison, WI, USA.
Abstract: Precise wiring of cortical circuits during development depends upon axon extension, guidance, and branching to appropriate targets. Motile growth cones at axon tips navigate through the nervous system by responding to molecular cues, which modulate signaling pathways within axonal growth cones. Intracellular calcium signaling has emerged as a major transducer of guidance cues but exactly how calcium signaling pathways modify the actin and microtubule cytoskeleton to evoke growth cone behaviors and axon branching is still mysterious. Axons must often pause their extension in tracts while their branches extend into targets. Some evidence suggests a competition between growth of axons and branches but the mechanisms are poorly understood. Since it is difficult to study growing axons deep within the mammalian brain, much of what we know about signaling pathways and cytoskeletal dynamics of growth cones comes from tissue culture studies, in many cases, of non-mammalian species. Consequently it is not well understood how guidance cues relevant to mammalian neural development in vivo signal to the growth cone cytoskeleton during axon outgrowth and guidance. In this review we describe our recent work in dissociated cultures of developing rodent sensorimotor cortex in the context of the current literature on molecular guidance cues, calcium signaling pathways, and cytoskeletal dynamics that regulate growth cone behaviors. A major challenge is to relate findings in tissue culture to mechanisms of cortical development in vivo. Toward this goal, we describe our recent work in cortical slices, which preserve the complex cellular and molecular environment of the mammalian brain but allow direct visualization of growth cone behaviors and calcium signaling. Findings from this work suggest that mechanisms regulating axon growth and guidance in dissociated culture neurons also underlie development of cortical connectivity in vivo.