A second career for a growth factor receptor: keeping nerve axons on target

September 12, 2008

LA JOLLA, CA - Neurons constituting the optic nerve wire up to the brain in a highly dynamic way. Cell bodies in the developing retina sprout processes, called axons, which extend toward visual centers in the brain, lured by attractive cues and making U-turns when they take the wrong path. How they find targets so accurately is a central question of neuroscience today.

Using the mouse visual system, a team of Salk Institute for Biological Studies investigators led by Dennis O'Leary, Ph.D., identified an unanticipated factor that helps keep retinal axons from going astray. They report in the Sept. 11 issue of Neuron that p75, a protein previously known to regulate whether neurons live or die, leads a double life as an axon guidance protein.

"Historically, we thought that factors that mediate cell survival and those controlling axon guidance were part of two separate processes," says O'Leary, a professor in the Molecular Neurobiology Laboratory, "But in this study we show a direct interaction between these two systems."

Collaborating with Kuo-Fen Lee, Ph.D., professor in the Clayton Foundation Laboratories for Peptide Biology, the O'Leary team observed a defect in mice genetically engineered to lack p75. Through their synaptic connections, retinal axons develop a two-dimensional map of the retina in their targets in the brain. In the mice lacking p75, retinal axons stopped short of their final target and formed a map that was shifted forward to the superior colliculus, a major visual center in the brain.

Such a defect in p75-null mice was puzzling: researchers have studied p75 for decades and found it associated with activities as varied as neuronal growth, survival, and degeneration. Axonal migration was not among them.

Todd McLaughlin, Ph.D., a senior research associate in the lab and co-first author, says that insight came in a eureka moment: "We realized that what we were observing in these mice was similar to what would happen if you deleted a gene called ephrin-A from the retina."

Unlike p75, ephrin-A was a well-characterized sender and receiver of axon guidance signals, but it lacked appendages normally seen on proteins controlling axon migration. p75, however, displayed those elements, suggesting that the proteins could pair up - one receiving the migration signal and the other transmitting it.

The research team then turned to biochemical analyses and with the added expertise of Tsung Song, a research associate in Dr. Lee's lab, obtained evidence that supported this hypothesis. The group found that ephrin-A and p75 complexes in axonal membranes and showed that when activated they could generate the signals required to guide axons and develop their map in the brain.

But the clincher was the "stripe assay," a classical screen for guidance molecules that repel growing axons. In it, an immature neuron is placed on a microscopic running track, just as it starts to develop an axon. When flanking lanes are carpeted with repellant factors, the sprouting axon bursts from the block but remains in its lane like a well-coached runner, avoiding neighboring tracks.

Constructing tracks made from the repulsive factor sensed by ephrin-A, the researchers confirmed that axons from normal retinal neurons stayed in their lanes when flanked by the repellant. But neurons from mice lacking p75 were unreceptive to repulsive cues: when placed on the track their axons meandered all over the field, crossing lanes and running down repellant-covered stripes.

Why retinal neurons missed the target in the p75-minus mice became clear: they lacked the cellular machinery to respond to critical repellant signals encountered in the brain and stopped migrating prematurely.

Among its myriad functions, p75's new role is a critical one. "Repulsion is probably the dominant force in axon guidance and a stronger influence than attraction," explains McLaughlin, noting that providing axons with a lot of options is not the way to build a brain. "Attraction is like finding the best seat in an empty movie theater, but repulsion is like picking the lone empty seat in a full theater."

"We have shown that ephrin-A cannot transduce an intracellular signal by itself and instead requires the co-receptor p75," summarizes Yoo-Shick Lim, Ph.D., a postdoctoral fellow in the O'Leary lab and co-first author. "This interaction could operate in numerous events in neural development."

O'Leary believes that identifying mechanisms underlying developmental events is fundamental to understanding the basis of any biological disorder. "These studies establish that two distinct molecular systems, neurotrophins and axon guidance, both critical for neural development directly collaborate to develop neural connectivity.

Findings such as these lend critical insight into how one might repair damage to the nervous system due to genetic defects, tumors or wounds to the brain or spinal cord," he says. "We hope one day to be able to repair these defects and get cells to form functional connections again."

Salk Institute

---

---

	From Axons to Identity: Neurological Explorations of the Nature of the Self (Norton Series on Interpersonal Neurobiology) by Todd E. Feinberg (Author) A leading neuroscientist offers an intriguing scientific journey to understanding the neurobiology of the self.What can dementia, delusions, and other neurological disorders teach us about how the brain creates personal identity and a unified sense of self? Here, a leading neurobiologist offers an intriguing scientific approach to understanding the neurobiology of the self. Drawing on both the latest neuroscientific research, as well as the author's decades of experience with neurological patients, From Axons to Identity examines the link between brain and identity in fascinating new ways. Dr. Feinberg presents case studies of individuals with brain pathologies and unusual psychiatric syndromes that cause them to deny parts of their bodies or believe in the presence of...
	Cell Biology of the Axon (Results and Problems in Cell Differentiation) by Edward Koenig (Editor) Recent years have witnessed striking advances in research on axons at a cellular level that substantially impact our current understanding of axonal biology. Newer findings and their ramifications are critically reviewed in the 16 chapters of this volume by authors highly qualified by virtue of their scientific contributions to research areas they know and write about. Five basic areas (I to V) germane to axonal biology are highlighted, beginning with (I) signaling interactions mediating myelination, and differentiation of axonal membrane domains; (IIa) issues surrounding organization and transport dynamics of neurofilaments in axons, (IIb) mechanisms regulating microtubule organization and dynamics, misregulation of which causes axonal degeneration, and (IIc) the roles actin binding...
	Gastroenterological Endoscopy by Anthony Axon (Author), John Baillie (Author), Hugh Barr (Author), Kenneth Binmoeller (Author) Gastroenterological endoscopy has experienced tremendous advancements in the last decade. In this outstanding book, you'll get state-of-the-art information on all therapeutic developments and innovations in the field. A top team of highly acclaimed gastroenterology specialists from around the world have come together under the editorial leadership of Meinhard Classen, Guido N.J. Tytgat, and Charles J. Lightdale to create this pace-setting atlas and reference work. The book gives you complete coverage of everything from basic examination techniques to the latest treatment strategies in gastroenterology. You'll learn how to recognize diseases and reach an accurate diagnosis for disorders of the GI tract. More that 1,800 illustrations, most in full-color, demonstrate theories...
	Essays in Literature and Ethics: Edited With a Biographical Introduction by William E. A. Axon (1889) by William Anderson O'Conor (Author) Originally published in 1889. This volume from the Cornell University Library's print collections was scanned on an APT BookScan and converted to JPG 2000 format by Kirtas Technologies. All titles scanned cover to cover and pages may include marks notations and other marginalia present in the original volume.
	Axon Growth and Guidance (Advances in Experimental Medicine and Biology) by Dominique Bagnard (Editor) This book proposes an updated view of the current knowledge of the molecular and cellular mechanisms ensuring axon growth and guidance. The introductory chapter will remind the readers of all the features of a growth cone and the mechanisms controlling its growth. From there, one enters a fabulous journey with a growth cone, a Tom Thumb story filled with molecular encounters and complex interactions leading to one of the most fantastic developmental achievements: the nervous system wiring.
	Let's Go to a Stock Exchange, by Gordon V. Axon (Author) When they visit a stockbroker's office, two children learn about the functions of a stockbroker, the differences between stocks and bonds, and the operation of the stock exchange.
	On General Gordon's Copy Of Newman's Dream Of Gerontius (1889) by William Edward Armytage Axon (Author) This book is a facsimile reprint and may contain imperfections such as marks, notations, marginalia and flawed pages.
	The Literary History of Parnell's 'Hermit' [ 1881 ] by William E. A. (William Edward Armytage) Axon (Author) Originally published in 1881. This volume from the Cornell University Library's print collections was scanned on an APT BookScan and converted to JPG 2000 format by Kirtas Technologies. All titles scanned cover to cover and pages may include marks notations and other marginalia present in the original volume.
	The Ancoats Skylark, and Other Verses: Original and Translated [ 1894 ] by William E. A. (William Edward Armytage) Axon (Author) Originally published in 1894. This volume from the Cornell University Library's print collections was scanned on an APT BookScan and converted to JPG 2000 format by Kirtas Technologies. All titles scanned cover to cover and pages may include marks notations and other marginalia present in the original volume.
	Stray Chapters in Literature, Folk-Lore, and Archaeology [ 1888 ] by William E. A. (William Edward Armytage) Axon (Author) Originally published in 1888. This volume from the Cornell University Library's print collections was scanned on an APT BookScan and converted to JPG 2000 format by Kirtas Technologies. All titles scanned cover to cover and pages may include marks notations and other marginalia present in the original volume.