A push-me, pull-you gene can tear down neurons and rebuild them to order so far in mice. It’s named Nna1, which stands for “Nervous-System Putative Nuclear Protein-Induced Upon Axotomy.” That last term, axotomy, means cutting the axons of neurons. In principle, Nna1 can splice those severed axons as good as new.
A paper in the current issue of Science, dated March 8, 2002, carries the title: “Purkinje cell degeneration (pcd) phenotypes caused by mutations on the axotomy-induced gene, Nna1.” Its senior author is developmental neurobiologist Jian Zuo, whose laboratory at St. Jude Children’s Research Hospital in Memphis, Tenn., focuses on mouse genetics of neurological diseases.
“In the overall picture,” Zuo told BioWorld Today, “we have identified an aberrant gene that is responsible for a classic mouse mutant that causes Purkinje cell degeneration. It’s been studied for some 40 years. This gene, which is defective in this strain of mice, shows a spectrum of very interesting neurodegenerative phenotypes. They include, most dramatically, cerebellar Purkinje cells, which are involved in controlling body movement. Once those cells were gone, the spontaneously mutant mouse started to be ataxic lurching and wobbling a lot.
“That behavior was the reason they were identified in the first place,” Zuo went on, “when people 30 or 40 years ago found these mice staggering around. They bred them into successive generations, and found out that this gene had to perpetuate its lineage by inheritance. In addition to the cerebellar ataxic phenotype, these mice also showed a very strong degeneration of other neurons, such as photoreceptors, which are involved in vision. These mice probably have an ongoing, progressive loss of vision because of dying photoreceptor cells. This phenotype is very reminiscent of retinitis pigmentosa in humans, in which most of the photoreceptors are lost.
“Moreover,” Zuo continued, “those mice suffered from olfactory bulb defects, which is a part of the brain involved in smelling odor recognition. Without that particular cell type, it’s likely the mice couldn’t smell well. Finally, the male mice could not produce normal forms of sperm. The cells were not correct in shape, even though their numbers were close to normal, but somewhat reduced. Therefore, most of the Nna1 mutant male mice couldn’t reproduce well. Their sperm defect resembles the human infertility symptom.”
No Horror Symptoms Yet From Human Homologue
In fact, the resemblance goes further. NNA1, a human homologue of the mutant mouse gene, has been pinpointed to the long arm of human chromosome 9. But no equivalent horrendous defects have surfaced. “We can only anticipate,” Zuo observed, “that there would be some sporadic cases rather than a large number of inherited patients. I have doubts about that because the mouse phenotype is so severe I don’t think there would be any similar human offspring. A very few sporadic cases would not be reproducing, and they would be reduced in number. We don’t have any records of human NNA1 gene defects yet. Of course, that’s the reason for publishing this paper to see if any other human geneticist consortium would have such collections of such patients that would map to this region. Then they could start searching for mutations, and really benefit science.
By screening the database of Celera Genomics Group, of Rockville, Md., Zuo recounted, “we narrowed this region down by genetic means to a very small segment of the mouse chromosome 13. Within that locus there are not a lot of genes, presumably, and we wanted to find what they were, in order to identify them. What we used to do in the past was sequence the whole bloody region a very labor-intensive, huge effort. Now Celera and also the public domain, the mouse sequencing genome project both did it. At that time, when we started analyzing this gene region, we purchased the license from Celera to use its database. And once we found this region, at about 1 megabase, we just searched for some homology between this mouse region through that database, which we downloaded, and the existing human public domain, to the long arm of human chromosome 9. We found six conserved genes,” Zuo recalled, “one of which we pinpointed, so that really was a revolutionary key point of the whole project.”
“In terms of this gene,” Zuo said, “it was quite ironic that we were working on this mutant, trying to identify this gene, and we found out in the region of chromosome 9 the genomic segment that must contain this mutant sequence. Then we learned that a segment of this same gene had been identified in a lab literally next door to my office. Jim Morgan, a co-author of this Science paper, with his colleagues, had been working on the spinal regeneration paradigm for some years. When you cut the spinal cord, or cord neurons are injured, Morgan found that its genes are activated turned on.
“The implication of that phenomenon is still uncertain,” Zuo noted. “We can only say it has been involved in some kind of regeneration paradigm the neurons trying to recover from the injury, the cut. So this supplied the conclusive evidence that the Nna1 gene is directly responsible for these Purkinje cell degeneration mice. That’s why it provides a very unexpected link between the neuronal degeneration and neuronal regeneration.
“We know this gene is involved in the spinal cord regeneration,” Zuo went on. “Now we found also that once mutated, it’s causing the neurons to die. So we can imagine sometime in the future, we can somehow manipulate this gene and its protein product in a way that it can activate when the neurons are under stress or injured or something. It can therefore regenerate some of the potentially dying nerve cells. So that’s the major implication of this discovery.
“Finding the defective gene in these mice,” Zuo suggested, “could shed light on the pathology of other neurological diseases in humans, such as Alzheimer’s and Parkinson’s, and retinitis pigmentosa. It might also help us better understand male infertility.”
“This find may also help physicians learn how to better treat nerve-degenerating accidents, such as head injuries and radiation-induced nerve damage in cancer treatment,” added developmental neurobiologist Morgan, who originally identified the Nna1 gene while conducting studies into nerve regeneration.