Cellular Strategies of Axonal Pathfinding

Abstract

Axons follow highly stereotyped and reproducible trajectories to their targets. In this review we address the properties of the first pioneer neurons to grow in the developing nervous system and what has been learned over the past several decades about the extracellular and cell surface substrata on which axons grow. We then discuss the types of guidance cues and their receptors that influence axon extension, what determines where cues are expressed, and how axons respond to the cues they encounter in their environment.T his article provides an overview of how growth cones respond to the cellular substrata and molecular cues they encounter as they extend through the developing nervous system. It elaborates on the primer by Kolodkin and TessierLavigne (2010) and touches on many of the topics covered in greater detail in the articles that follow. The first sections describe how axons extend in a directed manner, the substrata on which they grow, interactions between pioneer and follower axons, and growth cone behaviors in emerging tracts and at decision points. The subsequent sections discuss examples of specific cues, their distributions, how their distributions are determined, and how growth cones integrate multiple cues during pathfinding. AXONS EXTEND IN VIVO IN A DIRECTED MANNERThe first person to visualize the growing tips of axons, Ramon y Cajal, recognized that axons for the most part grow very efficiently towards their ultimate targets. He was a strong advocate for axons finding their way in response to chemotactic cues:"If one admits that neuroblasts are endowed with chemotactic properties, then one might also imagine that they are capable of ameboid movements, initiated by factors secreted from epithelial, neural, or mesodermal elements. As a result, their processes may be oriented in the direction of chemical gradients, and thus guided to the secreting cells" (Ramon y Cajal 1892; trans. English, 1995).This surprisingly modern outlook emphasizing directed guidance was temporarily derailed by the views of Weiss during the 1920s and 1930s. He first argued that functional specificity did not arise as a consequence of specific axonal connections (Weiss 1936), and later argued that nonspecific mechanical guidance cues play a predominant role in guiding axons and organizing them into nerves and tracts

Roles of innervation in developing and regenerating orofacial tissues

“…At this stage, distances are much shorter than in late embryogenesis, allowing the pioneer axons to reach their targets easily. Pioneer axons indicate the routes that the trailing axons must follow in order to successfully innervate the target tissue [7]. Secreted signalling molecules that are expressed in various locations of the developing head guide growing axons.…”

“…Furthermore, axonal behaviour is influenced by the composition of the extracellular matrix (ECM) and the cells that the axons encounter during their growth. ECM and neighbouring cells can exert stimulatory or inhibitory effects on axonal growth, depending on the specific receptors expressed in the various neuronal populations [7] (Fig 1a). Adhesive proteins that either allow or block adhesion to the ECM or cells ensure a type of axonal guidance.…”

“…Homophilic interactions between these molecules are the basis of a strong interaction between pioneer axons and the trailing axons that will later innervate the target tissue. These molecules also mediate the repulsion between pioneer axons and axons not belonging to the same nerve, thus avoiding inappropriate innervation of a given tissue/organ [7].…”

“…The most notable among these molecules are the semaphorins, netrins and ephrins. Semaphorins are membrane-associated proteins that generally inhibit axonal growth [7]. Netrins are laminin-related secreted chemotactic molecules that can either attract or repel axonal growth, depending on the receptor (i.e.…”

“…Alternatively, guidance molecules can be bound to cell surfaces (most of the semaphorins and all ephrins) [7], allowing the growing cones to interact only with cells that are expressing them (Fig 1b). Membrane-associated molecules can also generate gradients via differential localization and expression on the cell surface of the various cell populations [7].…”