Target Selection by Cortical Axons: Alternative Mechanisms to Establish Axonal Connections in the Developing Brain

Abstract

We have described our studies of the development of projections from layer 5 of the rat neocortex to subcortical targets in the midbrain and hindbrain. The major points are briefly summarized here. 1. Layer-5 neurons extend a primary axon out of cortex and along a spinally directed trajectory, bypassing all of their targets in the midbrain and hindbrain. These targets are later contacted exclusively by collaterals formed by a delayed interstitial branching of the primary axon, not by growth cone bifurcation. 2. Collateral branches only form at stereotypic positions, not randomly along the length of the axon. Thus, specific cues identify branch points, and the length of the primary axon well behind its growth cone responds to these cues. 3. Layer-5 neurons in diverse areas of cortex initially develop the same basic set of collateral branches, although they will permanently retain different subsets of the initial common set. Therefore, branch cues are recognized by layer-5 neurons independent of whether the collateral projection formed is functionally appropriate for the cortical region in which the neuron resides. 4. In vitro and in vivo evidence indicates that one of the major branches, which forms the corticopontine projection, is induced and directed into its target, the basilar pons, by a diffusible, target-derived, tropic signal. Thus, a chemotropic cue promotes recognition of the basilar pontine target by the primary layer-5 axons. 5. In this system, then, target selection is not the responsibility of the growth cone of the primary axon.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereotyped Axon Pruning via Plexin Signaling Is Associated with Synaptic Complex Elimination in the Hippocampus

“…The stereotyped pruning of long axon collaterals in the vertebrate CNS is a widespread phenomenon that has been described for Ͼ20 years (Innocenti, 1981;Stanfield et al, 1982;O'Leary et al, 1990); until now, however, the cellular mechanisms were unknown. In particular, it was unclear whether long axon collaterals were capable of forming synaptic contacts and what cellular processes were involved in the loss of the synaptic contacts (if they formed) and their axons as they were eliminated.…”

“…In the CNS, the construction of precise circuitry is often preceded by a stage of development that involves the formation of collateral branch projections off an axon to ensure proper coverage of most potential synaptic targets (Purves and Lichtman, 1980;O'Leary, 1987;O'Leary et al, 1990;Kantor and Kolodkin, 2003;Luo and O'Leary, 2005). As a consequence, some of the long collateral projections that extend to transient but inappropriate locales are selectively removed in a stereotyped manner to ensure that proper targeting of axons is maintained.…”

“…In stereotyped pruning, the removal of subsets of inappropriately targeted long axon collaterals is often predictable because the transient branches can be identified before their removal (Chalupa and Killackey, 1989;O'Leary et al, 1990;Weimann et al, 1999;Lee et al, 2000;Bagri et al, 2003;Kantor and Kolodkin, 2003;Watts et al, 2003). In addition, the length of axon collaterals that undergo process elimination in stereotyped pruning often exceeds hundreds of micrometers (Chalupa and Killackey, 1989;O'Leary et al, 1990;Bagri et al, 2003); in contrast, the pruning of terminal arbors at the NMJ and the cerebellum (Lohof et al, 1996;Sanes and Lichtman, 1999;Lichtman and Colman, 2000) involves a few micrometers of branches.…”

Guidance Molecules in Axon Pruning and Cell Death

“…This pruning seems to rely on normal input, as altering visual activity feeding into the projecting neurons leads to profound pruning defects (Dehay et al 1989;Innocenti and Price 2005;Koralek and Killackey 1990;Shatz 1977). Another well-studied example of large-scale stereotyped pruning in the cerebral cortex is the refinement of subcortical projections arising from the visual and motor cortices (O'Leary et al 1990;O'Leary and Koester 1993;Stanfield 1992;Stanfield et al 1982) (Fig. 2B-2).…”

Axon Branching Requires Interactions between Dynamic Microtubules and Actin Filaments

“…Axons are guided in new directions by reorientation of their growth cones as well as extension of collateral branches (O'Leary et al, 1990). We have shown previously (Szebenyi et al, 1998) that cortical axon branching occurs in vitro through changes in growth cone morphologies and behaviors.…”