Developmental Biology

Edited by Karen Young Kreeger H. Roelink, A. Augsburger, J. Heemskerk, V. Korzh, S. Norlin, A. Ruiz i Altaba, Y. Tanabe, M. Placzek, T. Edlund, T.M. Jessell, J. Dodd, "Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord," Cell, 76:761-75, 1994. (Cited in nearly 90 publications as of February 1996) Comments by Henk Roelink, University of Washington SIGNALS FROM SONIC HEDGEHOG: Using cDNA, University of Washington's Henk Roelink and colleagues describing the genetic control of cell patterning in verebtrate embryos. This paper describes how the vertebrate version of the hedgehog gene-as expressed by the notochord (an embryonic structure)-induces the formation of floor plate cells and motor neurons in the developing embryo. These cell types are generated in the ventral, or underside, half of the neural tube, an embryonic structure that gives rise to the vertebrate nervous system. These investigations are in part related to the 1995 Nobel-Prize-winning research in developmental biology by Christiane Nusslein-Volhard and Eric Wieschaus (K.Y.Kreeger, The Scientist, Nov. 13, 1995, page 1). "They identified mutations in genes important for the correct patterning [spatial and temporal development] of cell types in developing fruit fly embryos, thereby indirectly uncovering a wonderful set of tools to study vertebrate development," explains Henk Roelink, an assistant professor in the department of biological structure at the University of Washington. "The reason we cloned the vertebrate homolog of the hedgehog gene is that homologs of other signaling molecules that control fruit fly development also appear to have important roles in vertebrate development," he explains. Roelink and his collaborators worked with versions of the hedgehog gene from zebrafish and rats. He was a postdoctoral fellow in the Howard Hughes Medical Institute lab of Thomas Jessell, a professor of biochemistry and molecular biophysics at Columbia University, until a few months ago. The work described in this paper was a collaborative effort with the labs of molecular biologists Jane Dodd, an associate professor at Columbia, and Thomas Edlund, a professor at the University of Umea in Sweden. Four other groups simultaneously cloned vertebrate hedgehog genes and published their results: Y. Echelard et al., Cell, 75:1417-30, 1993; S. Krauss et al., Cell, 75:1431-44, 1993; R.D. Riddle et al., Cell, 75:1401-16, 1993; and D.T. Chang et al., Development, 120:3339-53, 1994. These papers have been cited in nearly 140, 100, 170, and 30 publications, respectively, as of February 1996. "At first we named the hedgehog homolog we cloned vhh-1, but now it is referred to as sonic hedgehog [shh]," notes Roelink. "The hedgehog field has exploded in the last few years. Our paper was one of those that reported the cloning of the gene, but it was the first to report an in vitro assay for gene activity. If you transplant notochord cells to different places around the neural tube, ventral cell types [such as motor neurons or floor plate cells] start to develop in the vicinity of the notochord. These experiments indicate that there's a signal coming from the notochord that induces ventral cell types in the neural tube. Interestingly, we found that shh was expressed in the notochord at the time it induces ventral cell types in the neural tube. "That discovery prompted us to investigate whether this signaling molecule-sonic hedgehog-was the actual inducer of ventral cell types. With a cDNA [complementary DNA] coding for shh, it was easy to generate cell lines expressing the shh protein. We found that cells expressing shh acquire the same properties as the notochord and were able to induce ventral cell types in neural plate explants [living tissue used in tissue culture] in in vitro assays." Roelink points to an important follow-up paper-done in collaboration with the lab of molecular biologist Phil Beachy at the Johns Hopkins University School of Medicine-which describes the purification and activity of the shh gene product (H. Roelink et al., Cell, 81:445-55, 1995). "With this purified hedgehog protein, we could now do dose-response experiments on neural plate explants. During development, cells near the notochord, a source of shh, differentiate into floor plate cells, and cells further away become motor neurons. So, it might be that high concentrations of shh presumably found close to the source give rise to floor plate cells and lower concentrations give rise to motor neurons. We found that exposing neural plate explants in vitro to high levels of shh induced floor plate cells, while a lower concentration of shh induced motor neurons. These findings suggest that shh acts at different concentration thresholds to control cell patterning in the ventral neural tube." Edited by Karen Young Kreeger

Developmental Biology

The Scientist Staff

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