Chemoaffinity in topographic mapping revisited – Is it more about fiber–fiber than fiber–target interactions?

Highlights

• Fiber–target chemoaffinity has missed the high robustness of topographic mapping.

• Older findings suggest the need for additional fiber–fiber chemoaffinity.

• In vitro and molecular data indicate both being due to ephrin/Eph interactions.

• Modeling based on these assumptions reproduces mapping rigidity and flexibility.

• The power of these mechanisms might explain the prevalence of topographic mapping.

Abstract

Axonal projections between two populations of neurons, which preserve neighborhood relationships, are called topographic. They are ubiquitous in the brain. The development of the retinotectal projection, mapping the retinal output onto the roof of the midbrain, has been studied for decades as a model system. The rigid precision of normal retinotopic mapping has prompted the chemoaffinity hypothesis, positing axonal targeting to be based on fixed biochemical affinities between fibers and targets. In addition, however, abundant evidence has been gathered mainly in the 1970s and 80s that the mapping can adjust to variegated targets with stunning flexibility demonstrating the extraordinary robustness of the guidance process. The identification of ephrins and Eph-receptors as the underlying molecular cues has mostly been interpreted as supporting the fiber–target chemoaffinity hypothesis, while the evidence on mapping robustness has largely been neglected. By having a fresh look on the old data, we expound that they indicate, in addition to fiber–target chemoaffinity, the existence of a second autonomous guidance influence, which we call fiber–fiber chemoaffinity. Classical in vitro observations suggest both influences be composed of opposing monofunctional guidance activities. Based on the molecular evidence, we propose that those might be ephrin/Eph forward and reverse signaling, not only in fiber–target but also in fiber–fiber interactions. In fact, computational models based on this assumption can reconcile the seemingly conflicting findings on rigid and flexible topographic mapping. Supporting the suggested parsimonious and powerful mechanism, they contribute to an understanding of the evolutionary success of robust topographic mass wiring of axons.

Introduction

The connectionist view of neural function holds that the discriminating powers of perception, cognition, and motor control are embodied in the connectional architecture of the brain. The staggeringly complex connectome can roughly be classified into local and long-range wirings. There are two fundamental types of long-range axonal connections: non-topographic and topographic projections (Fig. 1A). In non-topographic projections, neuronal specification determines axonal destination, which is why they might also aptly be dubbed “typographic” projections. Their investigation has gained momentum only after the elucidation of the molecular organization of the prototypic olfactory system [1], [2], [3], because neuronal specificity is not similarly obvious in other non-topographic systems. Topographic projections, in contrast, are characterized by the preservation of spatial neighborhood relationships upon mapping, and examples are abundant. The topographic organization of the visual, auditory, somatosensory and motor systems have gained textbook prominence, but also deep inside the brain neighborhood preserving projections constitute a prevailing connectional motif [4], possibly because of its optimal wiring economy [5].

The developmental self-organization of the wiring first brings about the impressive computational capabilities of the brain and prearranges the tokens of the world eventually occurring to cognition. The elucidation of the pattern forming mechanisms of axon guidance has therefore intrigued neuroscientist for decades.

The systematic investigation of the mechanisms generating topographic projections originates in the early 1940s from the seminal work of Roger W. Sperry. He established the retinotectal projection, i.e., the axonal connection between the retinal ganglion cells (RGCs) of the eye and the dorsal midbrain (tectum) in vertebrates, as an experimentally amenable model, hoped to be a more general paradigm. The retinotectal projection faithfully maps the retinal output onto the next level of the visual pathway. The global orientation of the retinotopic map (Fig. 1B) results in the projection of the temporal/nasal (t/n) and dorsal/ventral axes of the retina onto the anterior/posterior (a/p) and lateral/medial axes of the tectum, respectively. We will focus on the projection along the a/p axis, because dorsoventral mapping is thought to be independent and is less well understood. The establishment of the retinotopic map has been studied in teleost fishes, amphibians, birds and mammals (mammalian homolog: retinocollicular projection) [6], [7], [8], [9], [10], [11]. In the chick, as an example, the axons of about 2.5 million RGCs per retina start to invade the tectum at its anteroventral pole at embryonic day 6 (E6) and spread out over the superficial fiber layer in posterodorsal direction until E13 to deploy the myriads of axonal terminals so that their arrangement ultimately reflects the neighborhood relationships of their retinal origins. When arrived near the topographically appropriate target, the axons dive down into the upper tectal layers and start to grow terminal arborizations [12]. Throughout this article, we will use the term “(axonal) terminal” collectively, to specify growth cones during development as well as maturing terminal arborizations. Interactions among these terminals and between the terminals and the target will be called “fiber–fiber” (FF) and “fiber–target” (FT) interactions, respectively, following a somewhat imprecise but common terminology. The mode of map formation differs somewhat between mammals and other vertebrates. In rats, the growth cones of RGC primary axons appear to be less responsive to a/p guidance cues, as most of them grow straight to the posterior end of the superior colliculus (SC). The correct termination zone is subsequently established by interstitial branching and elimination of the overshoot of the primary axon [13]. In lower vertebrates, in contrast, the growth cones of primary axons immediately target their destination [14]. Despite some overshoot [15], growth cones of chick RGC axons are exceedingly sensitive to the topographic guidance cues and the extent of overshooting is much more limited than in mammals [16]. It probably merely mirrors the general imprecision of primary targeting.