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INTRAFLAGELLAR TRANSPORT Researchers at the University of California, Davis, have for the first time seen a motor protein moving cargo during intracellular transport in a living organism. "This provides a potentially very exciting assay for studying motor proteins generally in vivo," says Jonathan M. Scholey, senior author of the study published recently in Nature (J.T. Orozco et al., "Movement of motor and cargo along cilia," Nature, 398 :674, April 22, 1999). Using fluorescence microscopy, Scholey and colleagues observed heterotrimeric kinesin-II motor protein driving the antiretrograde transport of macromolecular complexes, known as rafts, along microtubule tracks from the base of the cilium to its distal tip. Then they watched as cytoplasmic dynein moved the rafts back in the retrograde direction in Caenorhabditis elegans. The ability to view intraflagellar transport (IFT) in organisms carrying mutations in the 25 genes essential for ciliary function in this system will also make it possible to determine which of the corresponding gene products are linked to the kinesin-II transport pathway, the authors suggest in the report. The study added further evidence to previous findings that IFT is important in the formation and maintenance of many cilia, including motile cilia, which drive the swimming of cells and embryos; nodal cilia that generate left-right asymmetry in vertebrate embryos; and sensory cilia, which detect sensory stimuli in some animals. "The question now is how motor-driven transport contributes to the assembly and maintenance of these structures," says Scholey. Since the genome sequence of C. elegans is essentially complete, it should be possible to work out components of the transport pathway involved in assembly, he adds, and "that may be applicable to motile cilia, such as in the respiratory tract [in humans] or sensory cilia, such as the connecting cilia in the retina. Since dysfunctions in those structures can give rise to respiratory disorders or visual impairment, there could be biomedical applications of this research down the road." Scholey and colleagues will continue to focus on C. elegans. "We'd really like to use the assay to [determine] the components of the transport pathways, to find out exactly what molecules are actually transported, and then get at the questions about mechanisms of these motors." --A.J.S. Rayl GENDER-SPECIFIC MEDICINE If a new journal is a sign of official recognition for a field, then gender-specific medicine has finally arrived. The bimonthly Journal of Gender-Specific Medicine is the official publication of the Partnership for Women's Health at Columbia University, which is a collaboration between the university's medical center and the private sector. Each issue includes several peer-reviewed research articles, plus columns on pharmacy matters, government policy, and law and ethics. Content goes well beyond babies, bones, and breasts, acknowledging what many have known for quite some time--that extrapolating the results of clinical trials from men to women is scientifically flawed. "There are basic biological differences between women and men in every major organ system. Through gender-specific medicine, we can better understand the physiological differences between men and women, and how to diagnose and treat diseases more effectively," says Marianne Legato, professor of clinical medicine, editor-in-chief of the journal, and cochair of a National Press Club meeting on gender and human sexuality held April 30. An article on dermatology, for example, points out how differences in ways that men and women wear their hair and clothing explains differences in locations of skin cancers. Wound healing is the same in both sexes according to thickness and composition of the stratum corneum, but studies with rats show that skin matures more slowly in males (M.G. Mercurio, "Gender and dermatology," Journal of Gender-Specific Medicine, 16-20, September 1998.) Areas evaluated in the journal include the psychosocial (depression, drug abuse, anxiety, and eating disorders) and common diseases (Alzheimer's, acute respiratory failure, and cardiovascular disease). --Ricki Lewis Photos courtesy of Juan Carlos Izpisua-Belmonte TRANSFORMATION Adding fibroblast growth factor (FGF) and Txb4 to anterior flank cells made a chicken embryo (1) sprout an extra leg (2) where a wing would normally grow. ON A LIMB Putting a gene thought crucial for leg formation into the wing area of a chicken embryo made legs grow where wings normally develop--but investigators are hesitant to credit that gene, Tbx4, with sole responsibility for determining limb formation. "There is not a single gene that can do that job alone," comments Juan Carlos Izpisúa-Belmonte, associate professor at the Salk Institute in La Jolla, Calif. "We're starting to unearth a cascade of genes that informs limb development." Still, two new studies make it clear that Tbx4 plays a crucial role in that cascade (J.K. Takeuchi et al., "Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds," Nature, 398:810-4, April 29, 1999) (C. Rodriguez-Estaban et al., "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity," Nature, 398:814-8, April 29, 1999). Both show that altering the gene's placement turns potential wings into legs. Earlier work from two groups implicated Pitx1 upstream of the process (M. Logan and C.J. Tabin, "Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity," Science, 283:1736-9, March 12, 1999) (D.P. Szeto et al., "Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development," Genes & Development, 13:484-93, Feb. 15, 1999). Izpisúa-Belmonte notes that the Pitx genes appear to act on the Tbx genes, with Pitx2 affecting symmetry, or "handedness," of organs. Still, determining the precise role of each gene may be tough, Izpisúa-Belmonte comments. "It's been very difficult to tease apart the contributions of individual genes and to show that a single gene carries the blueprint for a leg or a wing," Salk investigator Concepcion Rodriguez-Estaban concurs. --Paul Smaglik CULTURING BRAIN MARROW Eminent biologist Archie Bunker nicknamed his son-in-law "Meathead" because he was "dead from the neck up." Researchers from the University of Tennessee, Memphis, have proven Archie wrong by culturing neural stem cells from the brains of adult humans ("brain marrow") (V.G. Kukekov et al., "Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain," Experimental Neurology, 156 [2], May 1999). The new work adds to similar findings in rodents and in the brains of cancer patients (P. Eriksson et al., "Neurogenesis in the adult human hippocampus," Nature Medicine, 4 :1313-7, November 1998). The Tennessee team cultured pieces of brain from the hippocampus and the subependymal zone--regions implicated in past work. Samples came from 10 patients aged 24 to 57 with intractable epilepsy. Small colonies--neurospheres--emerged after seven to 10 days in culture. A battery of tests to identify molecular markers, plus the fact that the cells grew under stem cell-friendly conditions and yielded neurons and glia when prompted to differentiate, indicate that they are stem or progenitor cells, the researchers conclude. "We believed these cells existed, but no one had isolated and expanded them in vitro to show that they are multipotential," says Dennis Steindler, a professor of anatomy and neurobiology. Such cells could be the seeds of brain tumors, yet also offer a way to treat neurodegenerative diseases. "These results mean that even senior persons have these cells. This gives us the opportunity in the future, as the research expands, to take a small biopsy specimen from a diseased person, grow the necessary cells, and then transplant them back," explains Valery Kukekov, scientific director of the Methodist health care brain marrow project. --Ricki Lewis A PENNY'S WORTH OF GAS Fresh-cut flowers are treated with silver solution to slow aging. The silver interferes with ethylene, an important regulator of plant growth and development. While membrane receptors for ethylene were identified several years ago, how they bind the gas is less obvious. With the silver effect in mind, Anthony Bleecker, professor of botany at the University of Wisconsin in Madison, wondered if a more biologically friendly metal such as copper could be important. Says Bleecker, "small gas molecules, if they bind to proteins, tend to do it through transition metals." To test the idea, Bleecker's research team fused part of an Arabidopsis gene encoding the active first 128 amino acids of the ETR1 receptor to a glutathione S-transferase "reporter" gene and inserted it into yeast, which normally doesn't bind ethylene (F.I. Rodriguez et al., "A copper cofactor for the ethylene receptor ETR1 from Arabidopsis," Science, 283 :996-8, Feb. 12, 1999). Membrane extracts of yeast transformed with the truncated gene bind the gas, while those transformed with the same sequence from an inactive gene (etr1-1) do not. Bleecker then tested the effect of copper--it enhances ethylene binding in the extracts 10- to 20-fold. ETR1 apparently functions as a dimer containing one copper ion, based on measurements of the metal in purified protein. Bleecker thinks a copper(I) cofactor is coordinated by key amino acids in one of three membrane-spanning alpha helices in the receptor; replacing cysteine or histidine at positions 65 and 69 in helix 2 eliminates binding. As for silver, it probably substitutes for copper, but the receptor can't pass the signal down the response chain once ethylene binds. Bleecker also wants to know how copper ions get to ETR1 as it's assembled inside the cell. Yeast contains a protein that carries copper to the Golgi apparatus, where another molecule imports it for attachment to maturing proteins. Yeast transformed with ETR1 but defective in the carrier/import system doesn't bind ethylene, presumably because it can't add the copper. Bleecker thinks plants contain a similar system. --Barry A. Palevitz SNIFFING OUT OLFACTION Combinatorial codes are a recurrent theme in maximizing information in living systems. For example, neuroscientists have long hypothesized that different combinations of receptors stimulated by odorant molecules tell the brain that an animal is smelling garlic, tar, or essence of skunk. Two reports shed light on olfaction using a dye that emits light when activated neurons admit a rush of calcium. Giovanni Galizia and colleagues at the Institute for Neurobiology in Berlin focused on the honeybee, because insects have only 160 glomeruli--clusters of dendrites and axons in the brain--that receive incoming odors, compared to thousands in mammals (C.G. Galizia et al., "The glomerular code for odor representation is species specific in the honeybee Apis mellifera," Nature Neuroscience, 2 :473-7, May 1999). "Each glomerulus gets input from hundreds of olfactory receptor cells, and from thousands of interneurons which interconnect the glomeruli," explains Galizia. The researchers immobilized 24 bees, exposed and dyed their brains, then puffed a smelly airstream past their antennae. The fluorescence pattern of brain slices revealed which glomeruli responded to clove oil, peppermint, orange, and various organic compounds. The bees lit strikingly similar mosaics of turned-on glomeruli for 30 odors. Yet the olfactory system is also redundant--a bee can detect most floral scents and pheromones using only 18 of its 160 glomeruli. Nor are the responses genetically hard-wired. "Honeybees can be trained to associate odors with a sugar reward. If they expect the reward, they extend their proboscis in response to the odor alone," adds Galizia. In a related report, Linda Buck, a Howard Hughes Medical Institute researcher at Harvard Medical School and colleagues there and at the Life Electronics Research Center in Amagasaki, Japan, used calcium imaging and RT-PCR to identify odorant receptors on isolated neurons from mice (B. Malnic et al.,"Combinatorial receptor codes for odors," Cell, 96 :713-23, March 5, 1999). Results confirmed three indications of a combinatorial olfactory code. Explains Buck, "A single receptor can recognize multiple odorants; a single odorant is typically recognized by multiple receptors; and different odorants are recognized by different combinations of receptors." --Ricki Lewis

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A. J. S. Rayl

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May 1999

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