August 17, 2009

From Nerve Roots to Plant Roots

Image panel shows that atlastin/RHD3 deficiency causes shortening of rat neurons and short, wavy root hairs in a plant At top, rat cortical neurons; at bottom, Arabidopsis roots. The left side shows normal neurons and root hairs. The right side shows the effects of atlastin/RHD3 deficiency.Neuron images courtesy of Dr. Craig Blackstone, NINDS. Arabidopsis images courtesy of Dr. John Schiefelbein, University of Michigan, Ann Arbor.

Sprouting. Branching. Pruning. Neuroscientists have borrowed heavily from botanists to describe the way neurons grow. A new study suggests the analogies may be more than superficial. Neurons and plant root cells may grow using a similar mechanism. The research sheds light on a group of inherited neurological disorders called hereditary spastic paraplegias (HSP).

HSP primarily affects corticospinal neurons, which extend projections called axons from the brain's cerebral cortex to the spinal cord. The longest corticospinal axons reach nearly all the way down the spinal cord—a distance up to about 3 feet—in order to control movement in the legs. In HSP, these long axons develop abnormally or degenerate later in life, causing muscle stiffness and weakness in the legs.

More than 40 genes have been implicated in HSP, but their roles are poorly understood. Mutations in the atlastin gene are one of the most frequent causes of HSP, accounting for about 10% of cases. In previous research, a team led by Dr. Craig Blackstone, an investigator at NIH's National Institute of Neurological Disorders and Stroke (NINDS), showed that atlastin has a role in axon growth. Blackstone's group set out to investigate further, with collaborators Dr. William Prinz of NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Dr. Tom Rapoport, a Howard Hughes Medical Institute investigator at Harvard Medical School.

A clue to atlastin's role in HSP came from another gene associated with the type of HSP caused by atlastin mutations. It encodes a protein that helps to form the large, net-like cellular structure known as the endoplasmic reticulum (ER). With both tubular and sheet-like sections, the ER is a complex cellular factory where molecules are made and packaged for shipping to their cellular destinations.

The researchers reported in Cell on August 7, 2009, that atlastin interacts with proteins known to be involved in forming the ER. Other experiments showed that atlastin itself is found at tubular regions of the ER. Furthermore, modifying the amount of atlastin produced by cells causes defects in ER formation.

These experiments suggest that atlastin is necessary for maintaining the shape of the ER in mammalian cells. An analogous protein called Sey1p, the researchers found, performs the same function in baker's yeast. They theorize that some forms of HSP might arise when the ER loses its complex shape and thus the ability to support the growth or maintenance of long corticospinal axons.

Several years ago, researchers found that similar ER defects in a plant widely used for agricultural research, Arabidopsis thaliana (mouse-ear cress), impair the growth of the plant's root hairs—the wispy, microscopic projections that grow from individual root cells.

Arabidopsis has a gene comparable to atlastin called Root Hair Defective 3 (RHD3). Mutations affecting RHD3 cause the plant to grow short, wavy root hairs.

Arabidopsis could prove to be a useful tool for investigating HSP. It's easy to raise in the lab, and the short root hairs of the RHD3 mutant can be readily observed. Blackstone says he hopes to collaborate with other scientists to develop strategies to correct root hair defects in the RHD3 mutant. These might provide valuable therapeutic insights into HSP.

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