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The roundworm C. elegans was used as a model in this research focused on dendrites, the string-like extensions of sensory nerves that penetrate tissues of the skin, eyes and other sensory organs.
PVD gene is essential for normal nerve branching
Our ability to detect heat, touch, tickling and other sensations depends on our sensory nerves. Now, for the first time, researchers at Albert Einstein College of Medicine of Yeshiva University have identified a gene that orchestrates the crucially important branching of nerve fibers that occurs during development.
The findings were published online in the journal Cell.
"The formation of dendritic branches—‘arbors’ as we call them—is vital for allowing sensory nerves to collect information and sample the environment appropriately.
"These arbors vary greatly in shape and complexity, reflecting the different types of sensory input they receive. The loss of dendritic complexity has been linked to a range of neurological problems including Alzheimer’s disease, schizophrenia and autism spectrum disorders."
Hannes BuelowPh.D., senior author of the Cell paper, associate professor of genetics at Einstein, also associate professor in the Dominick P. Purpura Department of Neuroscience.
The Human Genome Project, completed in 2003, revealed that humans possess some 20,500 genes and determined the DNA sequence of each. But for many of those genes, their function in the body has remained unknown. The newly identified gene falls into this "previously unknown function" category. In fact, the gene belongs to an entire class of genes that had no known function in any organism.
One way to learn what genes do is to study a model organism like the roundworm, which possesses a similar number of genes as people but only 956 cells, of which 302 are nerve cells (neurons). By knocking out or mutating roundworm genes and observing the effects, researchers can obtain insight into how genes influence the animal’s structure or physiology.
The Einstein scientists were looking for genes that organize the structure of the developing nervous system. They focused on a pair of roundworm sensory neurons, known as PVD neurons, which together produce the largest web of dendrites of any neurons in the roundworm—a sensory web that covers almost the entire skin surface of the worm and detects pain and extreme temperatures.
"The formation of dendritic branches — 'arbors' as we call them — is vital for allowing sensory nerves to collect information and sample the environment appropriately."
Hannes Buelow, Ph.D.
Suspecting that a gene acts in the skin to "instruct" nearby dendrites to branch, the researchers set out to identify the one responsible. To find it, they induced random mutations in the worms, singled out those worms displaying defects in PVD dendrite branching, and then identified the gene mutations that caused the defective branching.
This lengthy procedure, known as a genetic screen, was carried out by Yehuda Salzberg, Ph.D., the study’s lead author and a postdoctoral fellow in Dr. Buelow’s lab.
The screening process revealed that four mutations in the same gene caused defective branching of PVD dendrites.
The researchers showed that this gene’s expression in the skin produces an extracellular protein that triggers normal branching of PVD dendrites during development.
The dendritic branches of PVD neurons had previously been described as resembling menorahs, so the Einstein scientists named this gene mnr-1 and dubbed its protein menorin, or MNR-1.
The mnr-1 gene’s newly identified function in orchestrating dendrite branching is presumably not limited to roundworms. Versions of this gene are present in multicellular animals from the simplest to the most complex, including humans. Genes conserved in this way, through millions of years of evolution, tend to be genes that are absolutely necessary for maintaining life.
Further study revealed that menorin synthesized in the skin was necessary but not sufficient to prompt PVD dendrite branching. The menorin protein appears to form a complex with SAX-7/L1CAM, a well-known cell-adhesion protein found in the skin and elsewhere in the roundworm. The researchers found evidence that dendrite branching ensues when this two-protein complex is sensed by DMA-1, a receptor molecule found on growing sensory dendrites.
"A fair amount was already known about factors within sensory neurons that regulate dendrite branching," said Dr. Buelow. "But until now, we knew next to nothing about external cues that pattern the sensory dendrites crucial to the functioning of any of our five senses. Hopefully, our success in finding two skin-derived cues that orchestrate dendrite branching will help in identifying cues involved in other sensory organs and possibly in the brain. Finding such cues could conceivably lead to therapies for replacing dendrite arbors depleted by injury or disease."
MNR-1/menorin, a conserved protein, functions in dendrite arborization
MNR-1/menorin is a skin-derived, contact-dependent cue
MNR-1 functions with SAX-7/L1CAM in the skin through the dendritic receptor DMA-1
Our results identify a neuron-target guidance system for sensory dendrites
Sensory dendrites depend on cues from their environment to pattern their growth and direct them toward their correct target tissues. Yet, little is known about dendrite-substrate interactions during dendrite morphogenesis. Here, we describe MNR-1/menorin, which is part of the conserved Fam151 family of proteins and is expressed in the skin to control the elaboration of “menorah”-like dendrites of mechanosensory neurons in Caenorhabditis elegans. We provide biochemical and genetic evidence that MNR-1 acts as a contact-dependent or short-range cue in concert with the neural cell adhesion molecule SAX-7/L1CAM in the skin and through the neuronal leucine-rich repeat transmembrane receptor DMA-1 on sensory dendrites. Our data describe an unknown pathway that provides spatial information from the skin substrate to pattern sensory dendrite development nonautonomously.
The paper is titled "Skin-derived cues control arborization of sensory dendrites in Caenorhabditis elegans." Other Einstein scientists involved in the research were Zaven Kaprielian, Ph.D., and graduate students Carlos A. Díaz-Balzac, Nelson Ramirez, Matthew Attreed, Eillen Tecle, and Muriel Desbois.
The work was funded in part by grants from the National Institute of General Medical Sciences (T32GM007288, T32GM007491), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD055380, P30HD071593, F31HD066967), the National Cancer Institute (P30CA013330) and the National Institute of Neurological Disorders and Stroke (F31 NS076243), all parts of the National Institutes of Health.
The authors report no conflicts of interest.
- See more at: http://www.einstein.yu.edu/news/releases/941/previously-unstudied-gene-is-essential-for-normal-nerve-development/#sthash.5MTY8EwN.dpuf
Original press releas: http://www.einstein.yu.edu/news/releases/941/previously-unstudied-gene-is-essential-for-normal-nerve-development/