Retinal axon divergence in the optic chiasm: dynamics of growth cone behavior at the midline [published erratum appears in J Neurosci 1995 Mar;15(3):following table of contents]

Abstract

To study how retinal ganglion cell axons diverge in the optic chiasm, the behavior of dye-labeled fibers was monitored in real time with video microscopy in an isolated preparation of embryonic mouse brain, with a focus on embryonic day 15–16. These real-time studies have revealed the dynamics of the growth of individual retinal axons, especially the tempo of extension and growth cone behaviors during divergence in the chiasm, a model for “decision” regions in developing pathways. Within the chiasm, retinal growth cones extend by saltatory growth, consisting of bursts of rapid advance alternating with pauses in extension. During pauses, growth cone appendages remain motile, and develop asymmetries prior to a change in the axis of growth. In a zone straddling the midline, retinal fibers, irrespective of destination, display long pauses for up to several hours, making small advances and retractions with no net extension. While crossed fibers ultimately progress through the midline, uncrossed fibers from inferior temporal retina develop wide-ranging branched growth cones, and then turn back to the ipsilateral side. Turns are effected by the selective retraction or micropruning of asymmetric foci of motile activity, and by the transformation of a backward-directed filopodium into a new growth cone. The behavior of retinal axons at the midline supports the hypothesis that this locus contains cues important for retinal axon divergence. Moreover, the observations of growth cone kinetics in the chiasm elucidate which growth cone forms seen in static preparations mediate growth cone turning, and suggest a model of axon navigation in decision regions in the intact nervous system.

Regulated Cleavage of a Contact-Mediated Axon Repellent

“…The kinetics of growth cone collapse and withdrawal when wild-type ephrin-A2 was used in this assay appear consistent with the rate of ephrin-A2 cleavage induced by clustered EphA3-Fc, especially considering that the rate of receptorligand association has to be factored into the EphA3-Fc experiments. The kinetics also appear comparable to real-time studies of axon behavior in vivo [for example, (6,8)] as well as to ephrin-mediated withdrawal induced by primary cultured neurons or glia in vitro (34). Our results show that a mutation that blocks ephrin cleavage does not prevent signaling leading to growth cone collapse but does inhibit axon withdrawal.…”

“…which are well-characterized cell surface axon repellents: The ephnns and their receptors are expressed at high density; the receptors do not appear to be down-regulated upon ligand binding; and the receptor-ligand interaction is mul-tivalent, has a low off rate, and has a high aEnity (2)(3)(4)(5). Despite this, axon detachment and termination of signaling presumably have to be efficient because axons explore their embryonic environment in a dynamic fashion, involving both advances and withdrawals (6)(7)(8).…”

A Direct Interaction of Axonin-1 with Ngcam-Related Cell Adhesion Molecule (Nrcam) Results in Guidance, but Not Growth of Commissural Axons

“…The strict coincidence of growth cone enlargement and preference reaction suggests that the two phenomena are functionally connected. Concurrent conclusions were drawn from observations in vivo, where morphological changes of growth cones reacting to particular choice points along their path have been described in fixed and living tissue (Godement et al 1994; Mason and Wang 1997). Whereas growth cones have a simple morphology while they are advancing along fiber tracts, they assume a more complex shape at choice points, such as the optic chiasm (Godement et al 1994; Mason and Wang 1997) and the floor plate (Bovolenta and Dodd 1990).…”

Low lead levels stunt neuronal growth in a reversible manner.

“…1 C-F). Lamellar growth cones are more likely to be in a nonmigratory, exploratory mode, rather than rapidly extending (26). The increased prevalence of lamellar growth cones suggests the lead exposure may have altered the extracellular environment in the tectum (27,28).…”