CELL BIOLOGY
Supporting stem cells
A major hurdle in the therapeutic use of stem cells involves determining the internal and external factors that give them unique properties such as immortality and sustainability. One cluster of genes that might play an intrinsic role, called the Polycomb-group (PcG) genes, encodes a set of multiprotein complexes called PcG complex 1 and 2. Genetic studies suggest a role for PcG complex 1 in many types of stem cells, but the molecular functions of this complex remain unclear. To investigate the function of PcG complex 1, Motoaki Ohtsubo et al. focused on Geminin—a protein recruited to PcG complex 1 and known to suppress DNA replication licensing—in mouse hematopoietic stem cells (HSCs). They found that PcG complex 1 acts as an E3 ubiquitin ligase for Geminin, tagging Geminin to induce its degradation and facilitating turnover of the protein. Because Geminin expression is higher in HSCs, Ohtsubo et al. say that it may be a key support molecule for HSCs, regulating their proliferation, differentiation, and genomic stability. The authors also suggest that regulation of Geminin by PcG complex 1 could provide a potential target for altering stem cell properties for therapeutic use. — M.M.
“Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity” by Motoaki Ohtsubo, Shin'ichiro Yasunaga, Yoshinori Ohno, Miyuki Tsumura, Satoshi Okada, Nobutsune Ishikawa, Kenichiro Shirao, Akira Kikuchi, Hideo Nishitani, Masao Kobayashi, and Yoshihiro Takihara (see pages 10396–10401)
ECOLOGY
Treeshrew has a tolerance for alcohol
Humans are generally assumed to be the only animals to regularly imbibe alcohol, but researchers have found that Malaysia's pentailed treeshrew (Ptilocercus lowii) subsists on a diet that is the equivalent of beer and may have been doing so for up to 55 million years. The treeshrew is believed to be similar to the last common ancestor of all living primates, raising the possibility that sensitivity to alcohol may not be exclusive to humans. The treeshrew feeds on the nectar of the flower buds of the bertam palm (Eugeissona tristis), which is fermented to an alcohol content of up to 3.8% by a symbiotic team of yeasts. The palm produces nectar year-round on a complex schedule that appears to maximize pollination by the treeshrews. Frank Wiens et al. videotaped regular nocturnal feeding sessions and followed the movements of radio-tagged treeshrews to estimate their alcohol intake. Without the special metabolic features that allow treeshrews to process their alcohol consumption, on any given night, a treeshrew would have a 36% chance of exceeding a blood alcohol level of 0.05%, a widely used threshold of inebriation in most mammals. Analysis of hair biomarkers corroborated the high intake levels. The authors say the treeshrew likely has an efficient biochemical pathway for degrading alcohol. — K.M.
Pen-tailed treeshrew with a radio collar.
“Chronic intake of fermented floral nectar by wild treeshrews” by Frank Wiens, Annette Zitzmann, Marc-André Lachance, Michel Yegles, Fritz Pragst, Friedrich M. Wurst, Dietrich von Holst, Saw Leng Guan, and Rainer Spanagel (see pages 10426–10431)
MEDICAL SCIENCES
Gene promotes survival of dormant tumor cells
Quiescent cancer cells scattered throughout the body can remain dormant for decades,surviving long after the primary tumor has been eliminated. Researchers have speculated that tumor cells may be able to switch to this “dormant mode” in response to environmental cues that halt cell division and enable adaptation to microenvironments and/or resistance to chemotherapy. Previous research showed that head and neck cancer patients or colon cancer patients with higher ATF6 mRNA levels in their primary tumors were more prone to be lymph node-positive or to relapse, respectively, leading Denis Schewe and Julio Aguirre-Ghiso to hypothesize that ATF6 was required for tumor cell survival during dormancy. The authors analyzed the molecular mechanism of the transcription factor and showed that ATF6 prolonged cancer cell survival through the up-regulation of Rheb and activation of mTOR signaling. Knocking down ATF6 led to the death of dormant cancer cells in vivo and increased the life span of mice with dormant tumor cells. The authors suggest that the ATF6α-Rheb-mTOR pathway could be a therapeutic target for eliminating dormant cancer cells. — B.T.
ATF6-induced Rheb signaling maintains S6 ribosomal protein phosphorylation (green).
“ATF6α-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo” by Denis M. Schewe and Julio A. Aguirre-Ghiso (see pages 10519–10524)
MICROBIOLOGY
Enter the herpesvirus
Herpes simplex virus type 1 (HSV-1) is the prototype of the herpesvirus family, which includes the varicella zoster and Epstein–Barr viruses. Herpesviruses are known to enter cells by membrane fusion, but researchers are working to understand the sequence of the molecular events that occur during fusion. Ulrike Maurer et al. used cryo-electron tomography to observe HSV-1 entry at the plasma membrane, capturing snapshots of viral particles contacting the membrane, adhering, fusing, and releasing the viral DNA capsid into the cell. Their experiments with adherent cells, however, revealed a limitation: side-on views of viral fusion were rare. To obtain comprehensive images, the authors prepared synaptosomes—small vesicles reconstituted from the ends of neurons. Viruses were allowed to interact with the synaptosomes and then flash-frozen onto the carbon grid. The authors searched for viruses caught in the act of fusion and accumulated a catalog of the different stages. They note that only one open, 25-nm-diameter fusion pore was found because the speed of pore opening made it difficult to observe. The authors suggest that the two structurally distinct poles of the asymmetric viral particle serve different functions: one being involved in entry and the other in viral assembly. — K.M.
Actin network (red) underlies the capsid (blue) and tegument (orange).
“Native 3D intermediates of membrane fusion in herpes simplex virus 1 entry” by Ulrike E. Maurer, Beate Sodeik, and Kay Grünewald (see pages 10559–10564)
NEUROSCIENCE
Bladder dysfunction may affect behavior
Overactive bladder is a disorder that affects the quality of life of 17% of the U.S. population. Elizabeth Rickenbacher et al. find that bladder dysfunction has debilitating neural effects in animals that may affect their cognitive abilities and behavior. The bladder sends neural signals to a brain region called Barrington's nucleus, which controls urination and may affect bowel movement. Barrington's nucleus also communicates with the locus coeruleus, which regulates arousal. The authors surgically obstructed the bladders of 12 rats and performed sham surgery on controls. Two to four weeks later, the authors observed the animals' urination patterns and conducted EEG measurements from the cortex. Two altered patterns of urination appeared in bladder-obstructed rats, but the change in brain activity compared with controls was similar in both cases. The neural response to a distended bladder decreased, possibly indicating a shift from brain to spinal control of the bladder. Also, two indicators of chronic arousal emerged in the cortex: decreased low-frequency EEG activity and elevated levels of theta waves. These findings provide a basis for investigating how disorders of internal organs can affect a patient's cognitive abilities and behavior, possibly disturbing sleep patterns, the authors say. — K.M.
“Impact of overactive bladder on the brain: Central sequelae of a visceral pathology” by Elizabeth Rickenbacher, Madelyn A. Baez, Lyman Hale, Steven C. Leiser, Stephen A. Zderic, and Rita J. Valentino (see pages 10589–10594)