Over the past three years, neurobiologists have flooded journals with papers unraveling this extraordinarily complex puzzle and deciphering the chemical guides that direct axons and lure them to their targets. This burst of progress was sparked in part by the long-sought discovery in 1994 of a diffusible chemo-attractant—netrin-1, a protein that attracts axons to the neuronal target cells that secrete it. The discovery was the work of Marc Tessier-Lavigne, a neurobiologist at the Howard Hughes Medical Institute (HHMI), University of California, San Francisco (UCSF), who has been at the forefront of research into axonal guidance factors for nearly a decade, with a particular focus on chemotropic guidance of axons. Hi1988 Nature paper on the subject, written with collaborators Thomas M. Jessell (also an HHMI investigator) and Jane Dodd of Columbia University, has attracted over 300 citations since its publication (see the table on page 4, paper #5). And two 1994 Cell papers from his laboratory on netrins have each averaged over 40 citations per year (see page 4, paper #1 and #2).

   Born in 1959, Tessier-Lavigne earned his bachelor's degree in physics from McGill University, as well as a B.A. in philosophy and physiology in 1982 from the University of Oxford, which he attended on a Rhodes Scholarship. In 1987 he earned his doctorate in retinal physiology and pharmacology from University College London. He began his studies of axonal guidance as a post-doc with Jessell at Columbia. In 1991 he moved to UCSF, where he is now a professor of Anatomy and of Biochemistry and Biophysics. He joined HHMI as an Assistant Investigator in 1994, becoming an Investigator in 1997.

From his office at UCSF,
Tessier-Lavigne spoke with Science Watch correspondent Gary Taubes.

  How did you first approach the problem of deciphering this labyrinth of guiding neuronal connections?

   Tessier-Lavigne: There have traditionally been three approaches. Historically the first was characterizing the complement of surface proteins present on axons, in the hope that some of them would be receptors for interesting guidance molecules. Another approach, which has borne considerable fruit, is the genetic approach in the nematode C. elegans, and the fruit fly Drosophila. The third is a kind of functional biochemical approach, and that's the one we used originally: to try to reconstruct axon guidance in vitro. We would then use those in vitro phenomena, in which axons are found to interact with their pathway and target cells, as bioassays to characterize and purify the molecules responsible for mediating the recognition events.
   To identify netrin-1, we used this cell-biological methodology in the context of the spinal column, focusing on one class of neurons, known as commissural neurons, that project to so-called floorplate cells of the spinal cord.

  What are the netrins, and exactly what do they do in the cells?

   Tessier-Lavigne: Netrins are relatively large proteins that are related to the extracellular matrix molecule, laminin. They are homologous to a portion of the laminin molecule, and likely evolved from some ancestral laminin molecule, but they are diffusible. Recently, in collaboration with the laboratory of Dr. Bill Skarnes at UC Berkeley, we were able to characterize a netrin-1 knockout mouse. In these mice, which are deficient in netrin-1 function, we find misrouting of commissural axons. So not only does netrin-1 have a profound effect on these axons in vitro, it is also clearly important in vivo in their normal guidance.

  Have researchers found counterparts to the netrins in other biological systems?

   Tessier-Lavigne: Yes. In C. elegans there's a protein called UNC-6, which is a netrin homologue. Even before we identified netrin-1, it was known that UNC-6 mutants have a misrouting of axons that is very analogous to that seen in commissural axon in netrin-1-deficient animals. And UNC-6 is found in the ventral midline of the nervous system of the nematode also, so there's a real parallel there. Netrins have also been found in Drosophila by our collaborators in the lab of Corey Goodman, an HHMI researcher at UC Berkeley, and by others, and again they appear to play a similar role in guiding axons to the midline. continued

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