Developmental Biology - Spinal Chord|
How Axons Enter the Spinal Cord
Researchers determine nerve fibers enter the spinal cord using "Cajalís battering ram" approach...
In zebrafish, it takes several days for nerve fibers to enter the wall of the spinal cord during embryonic development. Information on how nerves begin at the spinal cord and enter the arm, could lead to regenerative therapies for people with injuries to their brachial plexus, that network of nerves that sends signals from your spinal cord to your shoulder, arm and hand.
Smith's group found axons break into the spinal cord using the Ramon y Cajal's battering ram approach where boundary cap cells act as a bridge for other axons to travel across and into the spinal cord wall.
Published in Nature Communications, researchers at the University of Notre Dame, Indiana, determined that the widely dismissed Cajal theory, developed early in the 20th century, is actually correct, serving as the first step in a two-pronged approach by which axon nerve fibers penetrate the spinal cord.
Cody J. Smith PhD, the Elizabeth and Michael Gallagher Assistant Professor of Biological Sciences, Notre Dame University Center for Stem Cells and Regenerative Medicine and Evan Nichols of the Department of Biological Sciences, University of Notre Dame, used zebrafish larvae to evaluate two theories.
One theory posed by Santiago Ramon y Cajal, a pioneer in modern cellular neuroscience, in the 20th century. Cajal suggested axons used a "battering ram" approach during early development, breaking a hole in the spinal cord wall. The hypothesis turns out to be correct. The results were surprising because Cajal didn't have access to today's microscopes, which can show in real time how the fiber enters the wall.
The battering ram approach, however, is just the first step. For several years, scientists have thought boundary cap cells, located within the boundary of the central and peripheral nervous system, were the driving force behind moving axons into the spinal cord. During the study, Smith's group found axons break into the spinal cord using Cajal's battering ram approach taking several days to penetrate the spinal chord wall. Only then can boundary cap cells enter and serve as a bridge for other axons to travel into the spinal chord.
Smith: "We went into this research interested in the basic science. How do these axons enter the wall of the spinal cord? But this is the lesson ó sometimes basic science can lead to discoveries that are completely unexpected, yet with potentially exciting benefits."
Sensory axons must traverse a spinal cord glia limitans to connect the brain with the periphery. The fundamental mechanism of how these axons enter the spinal cord is still debatable; both Ramon y Cajalís battering ram hypothesis and a boundary cap model have been proposed. To distinguish between these hypotheses, we visualized the entry of pioneer axons into the dorsal root entry zone (DREZ) with time-lapse imaging in zebrafish. Here, we identify that DRG pioneer axons enter the DREZ before the arrival of neural crest cells at the DREZ. Instead, actin-rich invadopodia in the pioneer axon are necessary and sufficient for DREZ entry. Using photoactivable Rac1, we demonstrate cell-autonomous functioning of invasive structures in pioneer axon spinal entry. Together these data support the model that actin-rich invasion structures dynamically drive pioneer axon entry into the spinal cord, indicating that distinct pioneer and secondary events occur at the DREZ.
Evan L. Nichols and Cody J. Smith.
The authors thank Marc Wolman, Crislyn DíSouza-Schorey, Bernard Kulemaka, David Hyde, and members of the Smith lab for their helpful comments and reagent guidance, Sam Connell and Brent Redford of 3i for fielding imaging questions, and Deborah Bang, Karen Heed, and Kay Stewart for zebrafish care. This work was supported by the University of Notre Dame, the Elizabeth and Michael Gallagher Family, the Alfred P. Sloan Foundation, Center for Zebrafish Research at the University of Notre, and Center of Stem Cells and Regenerative Medicine at the University of Notre Dame.
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Sensory pioneer axons contact Dorsal Root Entry Zone (DREZ) before arrival of boundary CAP Cells.A
Diagram of Dorsal Root Ganglia (DRG) and DREZ following pioneer axon entry. Measurements are
taken from B
Distance from soma-ensheathing glia to DREZ and length of pioneer axon at 72 Hours
Post Fertilization (hpf). C
Confocal z-projection frames of a Tg(ngn1:gfp); Tg(gfap:nsfb-mcherry) Zebrafish stained for Sox10 protein at 56 hpf shows absence of Sox10 at DREZ. D
Quantification of the number of Sox10+ cell bodies located in DRG and at DREZ at 56 hpf. SEM is shown, n = 25 DRG.