Gaining Headway in Brain Growth

The Faculty of 1000 is a Web-based literature awareness tool published by BioMed Central. It provides a continuously updated insider's guide to the most important peer-reviewed papers within a range of research fields, based on the recommendations of a faculty of more than 1,400 leading researchers. Each issue, The Scientist will publish a list of the 10 top-rated papers from a specific subject area, as well as a short review of one or more of the listed papers. We will also publish a selection of comments on interesting recent papers from the Faculty of 1000's output. For more information visit www.facultyof1000.com. How a vertebrate's neural system develops, both its physical (neural) development, and the progenitor cells' scripted differentiation (neural induction), is a bit of a black box. Some of the required signaling molecules are known, but as with many biological systems, the more one digs, the more complexities one finds. F1000 Top 10All of Biology 1. W.M. Gray et al., "Auxin regulates SCFTIR1-dependent degradation of AUX/IAA proteins," Nature, 414:271-6, Nov. 15, 2001. 2. A. Trumpp et al., "Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo, Science 294:2186-9, Dec. 7, 2001. 3. L. Trusolino et al., "A signaling adapter function for *6ß4 integrin in the control of HGF-dependent invasive growth," Cell, 107:643-54, Nov. 30, 2001. 4. P. Bouillet et al., "Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim," Developmental Cell, 1:645-53, November 2001. 5. P. Gönczy et al., "zyg-8, a gene required for spindle positioning in C. elegans, encodes a doublecortin-related kinase that promotes microtubule assembly," Developmental Cell, 1:363-75, September 2001. 6. S. Urban et al., "Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases," Cell, 107:173-82, Oct. 19, 2001. 7. E.M., Pera et al., "Neural and head induction by insulin-like growth factor signals," Developmental Cell, 1:655-65, November 2001. 8. J. Rosenblatt et al., "An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism," Current Biology, 11:1847-57, Nov. 27, 2001. 9.E.A. Lundquist et al., "Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis," Development,128:4475-88, November 2001. 10. X. Morin et al., "A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila," Proceedings of the National Academy of Sciences, 98:15050-5 Dec. 18, 2001. Previous research in frog embryos showed that inhibiting the signaling pathway of bone morphogenetic proteins (BMP) and of a secreted glycoprotein, known as Wnt, is enough to induce head formation and the neural cells' proper differentiation. An embryonic region known as Spemann's organizer is the mastermind, dispensing out antagonists that block the pathways. But evidence found in the 1960s hinted that these inhibitors were not the whole story.1 Researchers found that a protein extract from guinea pig liver could induce forebrain development, and no Wnt or BMP inhibitors since described have matched the physical characteristics of the molecule delineated in the 1962 paper. That prompted a team led by Eddy de Robertis, a professor of biological chemistry and a Howard Hughes Medical Institute investigator at the University of California, Los Angeles, to screen frog embryos for other secreted proteins capable of influencing neural development or neural induction. The team's work produced a paper that ranked No. 7 in the Faculty of 1000's "All of Biology" Top 10 list for Jan. 4.2 One of the proteins his team found was insulin-like growth factor-binding protein 5 (IGFBP-5), which had never been studied in the context of early development. Previous work had shown that IGFBP-5 could act as both an agonist and antagonist of IGF, and the team decided to see which role it performed in the developing neural cells. To the team's surprise, IGFBP-5 mRNA caused the frog embryos' head regions to grow larger. "The finding that IGF signaling mimicked [Wnt and BMP signal inhibition], and was involved in head development, and—as we later found—in neural development, was a great surprise," says Edgar Mathias Pera, who is a postdoc in de Robertis' lab. "The finding doesn't exclude [the importance of] BMP and Wnt signaling; IGFBP-5 may be a positive-inducing signal.... Our work now shows that IGF, as an active signaling pathway, can mimic these processes and lead to both neural induction and neural development." The neural induction finding is even more exciting than the head development discovery, according to Pera, because of its potential therapeutic applications involving embryonic or adult stem cells. "The prospect of IGF being able to direct anterior neural cell fates, that's what we regard as very essential," he says. "There is no molecule to my understanding that is able to actually induce a forebrain-like neuron. We are far away from saying that IGF is able to convert a neural progenitor into a forebrain cell type, but we hypothesize that this may be the case," he explains. Pera doubts that this is the last word on neural induction and development activators. Instead, Pera says he believes that more activators are out there, awaiting discovery. A few years ago, Richard Harland of the University of California, Berkeley, published a paper3 in which he discussed as-of-yet unidentified molecules that he believes to be involved in neural induction. It still is not clear whether IGF is the molecule responsible for the activity seen by the 1960s researchers, but it does bear similarities in its physical properties, Pera notes. For the near future, at least, it seems likely that the closer researchers look at neural induction and neural development, the foggier these key processes will continue to appear. Jim Kling (jkling@nasw.org) is a freelance writer in Washington, DC. References 1. L. Saxén et al., Primary Embryonic Induction, Academic Press Inc. Ltd.: London, 1962, pp. 119-35. 2. E.M. Pera et al., "Neural and head induction by insulin-like growth factor signals," Developmental Cell, 1[5]:655-65, November 2001. 3. R. Harland, "Neural induction," Current Opinion in Genetics and Development, 10:357-62, 2000.

Gaining Headway in Brain Growth

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