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Embryonic development of the buffy flower bat, showing progressive growth of limbs
Image Credit: Courtesy of Karen Sears

Fats help organize spinal cord

Healing spinal cord damage is incredibly difficult. Torn neurons must reconnect with precision, which we cannot make happen - as yet. But, scientists at the RIKEN Brain Science Institute in Japan have discovered that lipids are as needed for the process of guiding axons, as proteins are — a discovery which may improve our attempts.

Published in Science, the study shows how phospholipids released by glial cells - nervous system cells that support neurons - control positioning of sensory neurons in the spinal cord. As they are derivatives of fat, they are hydrophobic - or are repelled by water. However, phosphate and amino groups on the lipid molecule make part of it hydrophilic - or drawn to water.
	Phospholipids are released by glial cells, the nervous system cells that support neurons and control the location of sensory neurons within the spinal cord. Image credit: Wikipedia

Axons are long extensions of neurons, and act as roads along which neural information travels. Their paths are initiated in response to each of our senses, but eventually branch off and become more diffuse. During development, they are either attracted or repeled by molecules which force them along specic chanels and in specific directions along the spinal cord.

"While many proteins are known to direct axon growth and network formation, we discovered glial cells have the ability to release membrane lipids [fats] released in specific patterns, which control axon migration and neuron organization. We found that a lipid called LysoPtdGlc has a major role in separating pain axons from position-sensing neurons."

Hiroyuki Kamiguchi MD, PhD, Neuronal Growth Mechanisms, Riken Brain Institute, and senior team leader.

Before reaching our brains, sensory information is initiated through our skin and muscles to travel along our spinal cord. Axons carry these minute electrical impulses initially all in one surge, but soon separates them. Impulses responsible for our ability to sense pain — nociception — travel along the sides of the spinal cord, while those that tell us the position, direction, and equilibrium involved — proprioception — travel close to the middle of the spinal cord.

Researchers were able to identify these pathways by experiments on chicken eggs. In a petri dish, they labeled chick spinal cord sections with molecular markers for LysoPtdGlc as well as for nociception and proprioception sensing neurons. They found LysoPtdGlc was located only near the midline of the spinal cord where proprioception or position-sensing axons are located.

The team hypothesized that when axons of pain-sensing or nociception neurons encounter LysoPtdGlc, they are repulsed from the midline of the spinal cord and forced to travel it's lateral, or side regions.

To test this theory, they looked at how cultured pain-sensing nociception neurons responded to the LysoPtdGlc lipid. When introduced within sections of chick spinal cord, they observed that LysoPtdGlc repelled axons from nociception neurons. This was confirmed when they next blocked access to the LysoPtdGlc lipid with an experimental antibody and prevented any nociception or pain-sensing neurons from being repelled.

The researchers then moved their experiments out of the petri dish and injected the antibody into the spinal cord of chick embryos. Their hypothesis that LysoPtdGlc was responsible for directing axon growth proved correct The axons of pain-sensing neurons were no longer repelled, and instead migrated into the region on the spinal cord reserved for position-sensitive neurons.

"Lipid research is technically difficult, but has the potential to uncover important biological processes not governed by protein-based mechanisms."

Hiroyuki Kamiguchi MD, PhD,

Having determinined that LysoPtdGlc's ability to repel pain-sensing nociception axons is controlled through a particular protein receptor on axons, the team tested over 100 receptors and found one — GPR55 — that responded well to LysoPtdGlc. This protein is also expressed in the spinal cord, and when the team labeled axons in mice with GPR55 turned off ( or supressed), they found pain-sensing axons mistakenly enter the upper-medial or middle portion of the spinal cord.

"With these findings we can begin to investigate whether this lipid-based signaling system can be a therapeutic target for spinal cord injury. I hope that our success here can facilitate interdisciplinary collaboration aimed at tackling other problems in biomedical research."

Hiroyuki Kamiguchi MD, PhD,

Abstract
Glycerophospholipids, the structural components of cell membranes, have not been considered to be spatial cues for intercellular signaling because of their ubiquitous distribution. We identified lyso-phosphatidyl-β-D-glucoside (LysoPtdGlc), a hydrophilic glycerophospholipid, and demonstrated its role in modality-specific repulsive guidance of spinal cord sensory axons. LysoPtdGlc is locally synthesized and released by radial glia in a patterned spatial distribution to regulate the targeting of nociceptive but not proprioceptive central axon projections. Library screening identified the G protein–coupled receptor GPR55 as a high-affinity receptor for LysoPtdGlc, and GPR55 deletion or LysoPtdGlc loss of function in vivo caused the misallocation of nociceptive axons into proprioceptive zones. These findings show that LysoPtdGlc/GPR55 is a lipid-based signaling system in glia-neuron communication for neural development.

Reference: Guy, AT et al. Glycerophospholipid regulation of modality-specific sensory axon guidance in spinal cord. Science, doi:

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