Lipids' Role In Nervous System Development
Blocking a signaling lipid can keep nerves from developing the arm-like extensions they need to wire the body and may even cause neurons to die, scientists have found.
The scientists hope this piece of the puzzle of how the central nervous system develops in the first place will one day help them repair loss from injury or disease.
It's already helped them understand the ailments of a spontaneous mouse mutant that has about 20 percent function of the protein that helps the lipid get to the cell surface so it can help axons grow, says Dr. Wen-Cheng Xiong, developmental neurobiologist and corresponding author on the study published in the November issue of Nature Cell Biology.
The mutant mouse is small and has motor neuron degeneration, with tremors, short limbs and a short life, she says. Before this new work, what the blocked lipid transfer protein regulated was still a mystery.
The lipids in question aren't those measured during an annual physical exam, rather those that help give shape and function to units within cells such as the nucleus and cell powerhouse, or mitochondria, she says.
"Traditionally people didn't think these lipids were regulated. They thought they were just there," says Dr. Xiong. "But what we found is this particular lipid is regulated; it's like a signaling molecule. Especially during axon growth, the dynamic regulation is more dramatic.".
She and her colleagues found the lipid is transferred to the cell surface at just the right time and place by phosphatidylinositol transfer protein-a, which humans also have. It's been known that a number of proteins can be regulated, especially signaling proteins that enable intracellular chatter. "Now we have found this protein regulates lipids and lipids also travel," Dr. Xiong says.
The mouse mutant is a clear example of what can happen when the lipids don't travel. The scientists also studied a similar mutant chick embryo that had reduced axon growth. For this paper, they added the zebrafish embryo, which forms most of its major organs within the first 24 hours and remains transparent for the first few days of life, to further document the role of these regulated lipids and their transfer protein.
When they injected an agent that blocks expression of a related lipid transport protein, the next day they could see the impact on axon growth and neuron survival, says Dr. David J. Kozlowski, developmental geneticist and director of the MCG Transgenic Zebrafish Core Laboratory. They looked at different levels of suppression, finding the greater the suppression, the greater the resulting defect. "It shows this protein is critical for development," Dr. Xiong says of repeated findings.
Next they'll use a version of the transgenic zebrafish that will enable them to watch axon development - or lack of it - in live embryos and in real time, Dr. Kozlowski says.
They also want to look at what happens to the lipid activity in an injury model. They already know some signaling proteins are disturbed.
MCG contributors included the laboratories of Drs. Xiong and Kozlowski as well as Dr. Lin Mei, program chief in Developmental Neurobiology and Georgia Research Alliance Eminent Scholar in Neuroscience.
Collaborating institutions include the University of Alabama at Birmingham; the Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Howard Hughes Medical Institute; and the Jackson Laboratory in Bar Harbor, Maine.
The work was supported by the National Institutes of Health.