Mechanisms and molecules of neuronal wiring: a primer

Abstract

The complex patterns of neuronal wiring in the adult nervous system depend on a series of guidance events during neural development that establish a framework on which functional circuits can be built. In this subject collection, the cellular and molecular mechanisms that underlie neuronal guidance are considered from several perspectives, ranging from how cytoskeletal dynamics within extending neuronal growth cones steer axons, to how guidance cues influence synaptogenesis. We introduce here some basic topics to frame the more detailed reviews in following articles, including the cellular strategies that define basic themes governing neuronal wiring throughout life, an enumeration of the molecular cues and receptors known to play key guidance roles during neural development, and an overview of the signaling mechanisms that transduce guidance information into growth-cone steering.

Figure 1.

The diversity of neuronal guidance mechanisms. Neuronal processes are guided by cues that can function at long and short distances to mediate either attractive or repulsive guidance.

Figure 2.

Netrins, Slits, and their receptors. A schematic depicting these cues and their receptors, including receptors required for attraction (DCC) and repulsion (UNC5 for Netrins; Robo for Slits). The key defines distinct molecular domains found in these proteins.

Figure 3.

Semaphorins and their receptors. Shown here are the five classes of vertebrate Semaphorins and the major holoreceptor complexes required for Semaphorin-mediated repulsive and attractive guidance responses. Not shown are invertebrate transmembrane class 1 and secreted class 2 Semaphorins, and several non-Plexin/Neuropilin Semaphorin receptors. The key defines distinct molecular domains found in these proteins.

Figure 4.

Ephrins and their Eph receptors. A schematic showing the major A and B classes of Ephrins and their EphA and EphB receptors. The key defines distinct molecular domains found in these proteins.

Figure 5.

Morphogens involved in neuronal guidance and their receptors. A schematic showing Shh and its receptors (Smo, Ptch, Boc, and CDO), and Wnts and their receptors (Frz and Ryk), all of which serve guidance functions. Not shown are BMPs and their receptors. The key defines distinct molecular domains found in these proteins.

Figure 6.

Cell adhesion molecules (CAMs). Shown here are members of two major classes of CAMs: N-cadherin and two members of the Ig superfamily, FasII and DsCAM. The key defines distinct molecular domains found in these proteins.

Figure 7.

Guidance-cue receptor signaling strategies. (A) Rho GTPases cycle between inactive GDP-bound and active GTP-bound states to regulate cytoskeletal dynamics. (B) Guidance-cue receptor activation can influence Rho GTPase activity through direct associations with GEFs or GAPs. (C) Direct association of activated guidance-cue receptors with other signaling molecules, including signaling-adaptor proteins or kinases, can initiate signaling cascades also capable of regulating cytoskeletal dynamics.

Figure 8.

Axon guidance cues serve both neuronal and non-neuronal functions.