Mark H. Hankin

How do retinal axons find their targets in the developing brain

Tissue culture studies show that cell survival and process outgrowth from retinal ganglion cells depend on the molecular composition of the substrates over which the neurites grow, and on diffusible factors present in the medium. Recent work has begun to show that at least some of these components might be interactive. Since the conditions in a culture dish, as well as the patterns of antigen expression on cells in vitro, can differ considerably from those encountered in vivo, it is important to design experiments in vivo that examine how growing neurites relate to their natural microenvironment. By the use of transplantation techniques, it has been possible to provide evidence for a comparable duality of substrate-dependent and target-derived controls of optic axon growth, which might provide insight into the normal developmental process.

Specific target-directed axonal outgrowth from transplanted embryonic rodent retinae into neonatal rat superior colliculus

We have investigated whether there is evidence of target-directed growth of retinal axons to the tectum, and whether the surface of the rostral brainstem is an obligatory substrate for growing optic axons by transplanting embryonic mouse retinae to the cerebral aqueduct of neonatal rats. Such retinae emit axons that grow dorsally through the brain parenchyma to reach the superficial layers of the superior colliculus either by running dorsally along the midline, or by following a dorsally directed, radially arching course through the brain parenchyma. Studies of the early outgrowth pattern from transplanted retinae, and comparison studies of the axonal outgrowth from similarly placed cortical grafts suggest that outgrowth of retinal axons is target-directed and specific to optic axons.

Induction of target-directed optic axon outgrowth: effect of retinae transplanted to anophthalmic mice

In previous work using neural transplants (Hankin and Lund, 1987) we demonstrated two basic components of optic axon outgrowth in the mammalian retinotectal system: one category of outgrowth utilizes the subpial margin of the rostral brain stem as a preferential substrate (as do normal retinotectal axons); the other type of outgrowth, from retinae embedded deep within the midbrain parenchyma, is distance-dependent and highly target-oriented, but shows little apparent substrate specificity. One explanation for this directed outgrowth is that it is in response to a diffusible factor emanating from cells in the superior colliculus. In the present study we use congenitally anophthalmic mice as recipients for retinal transplants to test whether prior optic innervation of the superior colliculus plays a role in establishing either component of outgrowth. We show that outgrowth along the subpial pathway from a graft placed on the surface of the brain stem can take place in the absence of prior innervation of the superior colliculus. The target-directed outgrowth exhibited by embedded grafts only occurs if the tectum is also innervated by a second graft placed on the surface of the brain stem. It is proposed that tectal cells produce a factor in response to optic innervation and that this directs the growth patterns of embedded grafts. This suggests that optic innervation is a necessary prerequisite for the superior colliculus to produce the proposed diffusible chemotropic signal. In normal development such a factor could function to improve the efficiency of target-finding by later growing optic axons, but it might serve a quite different role, encouraging branching and trophic maintenance of the optic pathway once it has reached the tectum.

Mechanisms of axonal guidance. The problem of intersecting fiber systems.

The complex patterns exhibited by axon fiber tracts in animals present an intriguing challenge in the study of morphogenesis. How are these patterns established? What mechanisms determine the routes that particular axon growth cones will follow during development? This chapter first outlines the major historical theories of axonal guidance. These classic theories and their modern counterparts are then discussed in relationship to the development of intersecting fibers systems. Can these theories explain intersection? The second part of this chapter discusses an in vivo paradigm in which it is possible to study the ontogeny of an intersecting system of fibers in the mammalian central nervous system. A possible mechanism for axonal guidance in this system is discussed.

Developmental and Functional Integration of Retinal Transplants with Host Rat Brains

The normal functioning of the visual system depends on the development and maintenance of precise patterns of connections between the component parts such that a specific light-driven input can generate an appropriate response from the animal. The developmental events responsible for the formation of connections depend not only on programs intrinsic to the neurons, but also on a variety of extrinsic factors. Modulation of such factors during development substantially alters anatomical connections and associated physiology and behavior.

Chapter 29 The development of retinal projections

Publisher Summary This chapter discusses the development of retinal projections. It presents new insights into the interrelation between target influences and other factors directing axonal outgrowth and the development of orderly retinotectal connections. During maturation of the mammalian retinotectal projection, it appears that optic axons are not initially influenced by target-derived cues but instead follow substrate cues close to the subpial margin of the rostral brainstem. Directed by a polarized distribution of “pathway markers,” these axons make their way toward the dorsolateral midbrain, and thereby reach the tectum. A number of cell-surface and extracellular molecules have been co-localized along the subpial margin and one or more of these may be important components in tectopetal growth along the subpial pathway. The retinal transplant studies also reveal an evidence of a target-directed growth pattern effective over limited distances that depend on the prior optic innervation of the superior colliculus. The establishment of an orderly retinotectal projection is not a simple process and may depend upon an elaborate interaction between substrate-dependent events and target-derived cues.

In Vivo Correlates of In Vitro Studies of Axonal Guidance: Retinal Transplantation in the Mammalian Retinotectal System

It is nearly 100 years since Ramon y Cajal first described the bulbous ends of immature axons (see Ramon y Cajal, 1937), and 80 years since Harrison (1910) provided convincing evidence that these structures were, indeed, growth cones. In the intervening time, a great deal of interest has been directed towards elucidating the mechanisms by which axons are first guided along their pathway of outgrowth to their target regions, and then are matched with appropriate sets of neurons to form functional synaptic circuits.