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Internal nutrient sensors play important roles in feeding behavior, yet their molecular structure and mechanism of action are poorly understood. Using Ca 2+ imaging and behavioral assays, we show that the gustatory receptor 43a (Gr43a) functions as a narrowly tuned fructose receptor in taste neurons. Remarkably, Gr43a also functions as a fructose receptor in the brain. Interestingly, hemolymph...
Ring NTPases of the ASCE superfamily perform a variety of cellular functions. An important question about the operation of these molecular machines is how the ring subunits coordinate their chemical and mechanical transitions. Here, we present a comprehensive mechanochemical characterization of a homomeric ring ATPase—the bacteriophage φ29 packaging motor—a homopentamer that translocates double-stranded...
The mammalian brain comprises a diverse variety of cell types. Fine characterization of specific subpopulations of neurons, however, has been a technical challenge. Here, Knight et al. describe an elegant technique for high throughput of molecular profiling of activated hypothalamic neurons.
Phage G1 gp67 is a 23 kDa protein that binds to the Staphylococcus aureus (Sau) RNA polymerase (RNAP) σ A subunit and blocks cell growth by inhibiting transcription. We show that gp67 has little to no effect on transcription from most promoters but is a potent inhibitor of ribosomal RNA transcription. A 2.0-Å-resolution crystal structure of the complex between gp67 and Sau σ A domain...
In this issue and in a recent issue of Cell, Vahedi et al. and Samstein et al. provide new insights into the strategies used to establish an enhancer landscape during development of cell lineages. They report that enhancer landscapes characterizing T cell lineages are pre-established and strongly influenced by environmental stimuli.
An unexpected role for a Mediator subunit, MED12, in resistance to multiple anticancer agents is revealed by Huang et al. Loss of MED12 confers drug resistance by activating transforming growth factor β (TGF-β) signaling. Inhibition of the TGF-β pathway resensitizes cells to therapeutic drugs, suggesting a new combinatorial cancer treatment.
Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically...
The origins and developmental mechanisms of coronary arteries are incompletely understood. We show here by fate mapping, clonal analysis, and immunohistochemistry that endocardial cells generate the endothelium of coronary arteries. Dye tracking, live imaging, and tissue transplantation also revealed that ventricular endocardial cells are not terminally differentiated; instead, they are angiogenic...
MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) guide Argonaute proteins to silence mRNA expression. Argonaute binding alters the properties of an RNA guide, creating functional domains. We show that the domains established by Argonaute—the anchor, seed, central, 3′ supplementary, and tail regions—have distinct biochemical properties that explain the differences between how animal miRNAs and...
The inactive X chromosome’s (Xi) physical territory is microscopically devoid of transcriptional hallmarks and enriched in silencing-associated modifications. How these microscopic signatures relate to specific Xi sequences is unknown. Therefore, we profiled Xi gene expression and chromatin states at high resolution via allele-specific sequencing in mouse trophoblast stem cells. Most notably, X-inactivated...
Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE...
The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our understanding of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphorylated in neurons activated by a wide range of stimuli...
The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ∼78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named...
Genome duality in ciliated protozoa offers a unique system to showcase their epigenome as a model of inheritance. In Oxytricha, the somatic genome is responsible for vegetative growth, whereas the germline contributes DNA to the next sexual generation. Somatic nuclear development removes all transposons and other so-called “junk” DNA, which comprise ∼95% of the germline. We demonstrate that Piwi-interacting...
Bacteria lack many of the features that eukaryotic cells use to compartmentalize cytoplasm and membranes. In this issue, Schlimpert et al. describe a new mechanism of spatial confinment in the bacterium Caulobacter crescentus that prevents the exchange of soluble and membrane proteins between the stalk and cell body.
Norrin/Frizzled4 (Fz4) signaling activates the canonical Wnt pathway to control retinal vascular development. Using genetically engineered mice, we show that precocious Norrin production leads to premature retinal vascular invasion and delayed Norrin production leads to characteristic defects in intraretinal vascular architecture. In genetic mosaics, wild-type endothelial cells (ECs) instruct neighboring...
All cellular proteins are subject to quality control “decisions,” which help to prevent or delay a myriad of diseases. Quality control within the secretory pathway creates a special challenge, as aberrant polypeptides are recognized and returned to the cytoplasm for proteasomal degradation. This process is termed endoplasmic-reticulum (ER)-associated degradation (ERAD).
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