Breathing is essential for survival, and under precise neural control. The vagus nerve is a major connection between lung and brain required for normal respiration. In a recent publication in Cell, the Liberles Lab used molecular and genetic approaches to deconstruct the sensory vagus nerve, identifying two small populations of sensory neurons that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping using Cre/LoxP technology revealed that these neurons densely innervate the lung and send long-range projections to different stereotyped brainstem targets. Optogenetic stimulation of one neuron type (P2ry1) acutely silences respiration, trapping animals in a state of exhalation, while activating another (Npy2r) causes rapid and shallow breathing. Activating P2ry1 neurons had no effect on heart rate and gastric pressure, other essential vagus nerve functions. Thus, the vagus nerve contains genetically definable labeled lines with different anatomical connections and autonomic roles. Specific manipulation of breathing-control neurons electrically or pharmacologically may impact airway diseases like asthma or apnea.
Congratulations to Tobi Walter, who was chosen from a group of 894 eligible applicants to be one of 26 newly-minted Howard Hughes Medical Institute (HHMI) Investigators! HHMI investigators will receive the flexible support necessary to move their research in creative new directions. The initiative represents an investment in basic biomedical research of $153 million over the next five years.
The scientists represent 19 institutions from across the United States. The new HHMI investigators – which include three current HHMI early career scientists -- were selected for their individual scientific excellence.
HHMI will provide each investigator with his or her full salary, benefits, and a research budget over their initial five-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. Their appointment may be renewed for additional five-year terms, each contingent on a successful scientific review.
HHMI encourages its investigators to push their research fields into new areas of inquiry. By employing scientists as HHMI investigators — rather than awarding them research grants — the Institute is guided by the principle of “people, not projects.” HHMI investigators have the freedom to explore and, if necessary, to change direction in their research. Moreover, they have support to follow their ideas through to fruition — even if that process takes many years.
The National Academy of Sciences recently announced the election of 84 new members and 21 foreign associates from 15 countries in recognition of their distinguished and continuing achievements in original research. Among this list is Fred Goldberg, Professor of Cell Biology. The National Academy of Sciences is a private, non-profit society of distinguished scholars. Established by an Act of Congress, signed by President Abraham Lincoln in 1863, the NAS is charged with providing independent, objective advice to the nation on matters related to science and technology. Scientists are elected by their peers to membership in the NAS for outstanding contributions to research. Congrats Fred!
The American Diabetes Association will present the Outstanding Scientific Achievement Award to Pere Puigserver, PhD. Supported by an unrestricted educational grant from Lilly USA, LLC, this prestigious award recognizes research in diabetes that demonstrates particular independence of thought and originality. Dr. Puigserver will be recognized with this honor at the Association’s 75th Scientific Sessions, taking place June 5-9, 2015, at the Boston Convention and Exhibition Center in Boston. Congrats Pere! For more information, click here.
Peter Cobb, an HMS IT Client Service Representative who supports Cell Biology, was recently named a "Harvard Hero." This Harvard University-wide employee recognition program is designed to recognize “above and beyond” achievement among Harvard’s high-performing staff and their many contributions to the University. Only 64 individuals from over 12,000 Harvard staff were selected as Harvard Heroes in 2015! Congrats to Peter!
On Thursday, April 23, 2015, Bruce Spiegelman, PhD, was awarded the 2015 InBev-Baillet Latour Health Prize, in recognition of his outstanding contributions to the field of metabolic disorders. Dr. Spiegelman received this award at the "Palais des Académies," in the presence of H.M. Queen Mathilde of Belgium. Congratulations to Bruce on receiving this prestigious honor!
Organisms across the evolutionary spectrum have evolved mechanisms to maintain the integrity of the cellular proteome. Among these mechanisms are spatial protein quality control pathways in which damaged and misfolded cellular proteins are actively sequestered at unique subcellular structures in response to acute stress. This mitigates the deleterious effects of these aberrant protein species, which can include advanced cellular aging and cytotoxicity leading to cell death. Despite the universal importance of such spatial control of the proteome, there is considerable mechanistic diversity throughout the evolutionary scale regarding how this control is achieved. In a recent publication in Cell Reports (Egan and McClintock et al., PMID 25865884) the Reck-Peterson Lab expanded on the known evolutionary diversity of spatial quality control mechanisms by examining the subcellular organization of heat-induced protein aggregates in filamentous fungi, which are of substantial health and economic importance and serve as a model for transport processes in other polarized eukaryotic cells. Using Aspergillus nidulans, the Reck-Peterson group found that protein aggregates are actively organized at periodic subcellular structures in a process dependent on microtubules and their associated motor dynein. In addition, they found that sustained stress and increased burdening of this spatial quality control pathway can lead to defects in other microtubule-based transport processes. Given the significance of protein aggregation and polarized transport in neurodegenerative disorders, as well as the pathogenicity of many filamentous fungi, this work suggests several avenues of further investigation for understanding and combating disease.
Doubling the compete sets of chromosomes, or tetraploidy, occurs commonly during organismal evolution and also is frequent in disease states, such as cancer. Theory suggests that increased chromosome sets might promote evolutionary adaptation, especially if many available beneficial mutations are dominant. Whole genome duplications can also alter cell physiology in poorly understood ways. For example, whole genome duplications often cause genetic instability. Using in vitro evolution of yeast, the Pellman group demonstrates that tetraploidy can increase the rate of evolutionary adaptation when cells are grown in a poor nutrient environment (published recently in Nature). Two different mathematical modeling approaches (collaborations with Franziska Michor’s and Roy Kishony’s labs) suggest that tetraploids have an increased rate of adaptive mutations and these mutations have stronger fitness effects. Whole genome sequencing of multiple evolved clones verified increased frequencies of mutations and chromosome rearrangements in tetraploids. A class of mutations was discovered that provide a fitness advantage only to the tetraploid strains. Together, these results provide quantitative analysis of the long discussed role of polyploidy in evolutionary adaptation.
Evolution experiments were performed by batch culture of genetically identical strains, differing only by ploidy. The experiment starts with a 50:50 mix of otherwise identical YFP and CFP-labeled cells. Deviation from 50% YFP cells indicates adaptation.
Neurons are among the most polarized cells in nature, having emerged more than a half-billion years ago in metazoans to receive, process, and transmit information. The basic instructions to polarize a neuron appear to be intrinsically encoded, but what drives neurons to their extreme morphology is largely unknown. In a recent article in Genes and Development, the Shi Lab describes a molecular program that induces the early morphology of neurons through a deeply conserved, metazoan-specific zinc finger protein Unkempt. They find that ectopic expression of Unkempt confers neuronal-like morphology to cells of different nonneuronal lineages, while its depletion in mouse embryonic brain disrupts the shape of migrating neurons. The authors show that Unkempt functions as a sequence-specific RNA-binding protein that targets coding regions of a defined set of ubiquitously expressed messages linked to protein metabolism and regulation of the cytoskeleton. They further demonstrate that RNA binding is required for Unkempt-induced remodeling of cellular shape and is directly coupled to a reduced production of the encoded proteins. Thus, during embryonic development, Unkempt controls a translationally regulated cell morphology program to ensure proper structuring of the nervous system.
Small RNA molecules are familiar as negative regulators of endogenous protein-coding genes, but their more deeply conserved function is to ensure genomic stability by keeping repetitive and parasitic elements in check. In the fission yeast Schizosaccharomyces pombe, small RNAs accomplish this task by guiding heterochromatin formation at DNA regions flanking the centromere of each chromosome. The small RNA effector complex that targets the heterochromatin machinery to pericentromeric domains, called RITS, includes an Argonaute protein and a subunit bearing glycine-tryptophan (GW) repeats. The GW motif is a feature of Argonaute-interacting proteins that is conserved across several kingdoms of life and in silencing pathways both nuclear and cytoplasmic. A recent publication from the Moazed Lab has now uncovered a mechanism of ordered assembly for the GW protein-containing RITS complex that prevents Argonautes not yet programmed with a guide RNA from associating with GW repeat-containing proteins. In addition, they show that the poorly characterized fungal protein Arb1 is essential for loading small RNAs onto the S. pombe Argonaute in vitro and for RITS assembly in vivo. Altogether, the results demonstrate that a GW protein can act as a sensor of an Argonaute’s small RNA loading state. Finally, the work suggests that GW proteins play an evolutionarily conserved role in restricting the recruitment of downstream silencing machineries as varied as RNA deadenylases and chromatin-modifying enzymes exclusively to mature, competent Argonaute complexes.
(Holoch and Moazed, Nat. Struct. Mol. Biol., PMID 25730778)