The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis

1. Download high-res image (273KB)
2. Download full-size image

     

A curated gene list for expanding the horizons of pigmentation biology

Over the past century, studies of human pigmentary disorders along with mouse and zebrafish models have shed light on the many cellular functions associated with visible pigment phenotypes. This has led to numerous genes annotated with the ontology term “pigmentation” in independent human, mouse, and zebrafish databases. Comparisons among these datasets revealed that each is individually incomplete in documenting all genes involved in integument‐based pigmentation phenotypes. Additionally, each database contained inherent species‐specific biases in data annotation, and the term “pigmentation” did not solely reflect integument pigmentation phenotypes. This review presents a comprehensive, cross‐species list of 650 genes involved in pigmentation phenotypes that was compiled with extensive manual curation of genes annotated in OMIM, MGI, ZFIN, and GO. The resulting cross‐species list of genes both intrinsic and extrinsic to integument pigment cells provides a valuable tool that can be used to expand our knowledge of complex, pigmentation‐associated pathways.     

The synergy between RSC,Nap1 and adjacent nucleosome in nucleosome remodeling

Eukaryotes have evolved a specific strategy to package DNA. The nucleosome is a 147-base-pair DNA segment wrapped around histone core proteins that plays important roles regulating DNA-dependent biosynthesis and gene expression. Chromatin remodeling complexes (RSC, Remodel the Structure of Chromatin) hydrolyze ATP to perturb DNA-histone contacts, leading to nucleosome sliding and ejection. Here, we utilized tethered particle motion (TPM) experiments to investigate the mechanism of RSC-mediated nucleosome remodeling in detail. We observed ATP-dependent RSC-mediated DNA looping and nucleosome ejection along individual mononucleosomes and dinucleosomes. We found that nucleosome assembly protein 1 (Nap1) enhanced RSC-mediated nucleosome ejection in a two-step disassembly manner from dinucleosomes but not from mononucleosomes. Based on this work, we provide an entire reaction scheme for the RSC-mediated nucleosome remodeling process that includes DNA looping, nucleosome ejection, the influence of adjacent nucleosomes, and the coordinated action between Nap1 and RSC.     

crm-1 facilitates BMP signaling to control body size in Caenorhabditis elegans

We have identified in Caenorhabditis elegans a homologue of the vertebrate Crim1, crm-1, which encodes a putative transmembrane protein with multiple cysteine-rich (CR) domains known to have bone morphogenetic proteins (BMPs) binding activity. Using the body morphology of C. elegans as an indicator, we showed that attenuation of crm-1 activity leads to a small body phenotype reminiscent of that of BMP pathway mutants. We showed that the crm-1 loss-of-function phenotype can be rescued by constitutive supply of sma-4 activity. crm-1 can enhance BMP signaling and this activity is dependent on the presence of the DBL-1 ligand and its receptors. crm-1 is expressed in neurons at the ventral nerve cord, where the DBL-1 ligand is produced. However, ectopic expression experiments reveal that crm-1 gene products act outside the DBL-1 producing cells and function non-autonomously to facilitate dbl/sma pathway signaling to control body size.     

Neurotropic EV71 causes encephalitis by engaging intracellular TLR9 to elicit neurotoxic IL12-p40-iNOS signaling

Brainstem encephalitis, a manifestation of severe enterovirus 71 (EV71) infection, is an acute excessive inflammatory response. The mechanisms underlying its development remain poorly understood. Usually neurotropic viruses trigger acute host immune response by engaging cell surface or intracellular receptors. Here, we show that EV71 engagement with intracellular receptor TLR9 elicits IL-12p40-iNOS signaling causing encephalitis in mice. We identified IL-12p40 to be the only prominent cytokine-induced at the early infection stage in the brainstem of mice subjected to a lethal dose of EV71. The upregulated IL-12p40 proteins were expressed in glial cells but not neuronal cells. To better understand the role of IL-12p40 in severe EV71 infection, we treated the EV71-infected mice with an antibody against IL-12p40 and found the mortality rate, brainstem inflammation, and gliosis to be markedly reduced, suggesting that the acute IL-12p40 response plays a critical role in the pathogenesis of brainstem encephalitis. Mechanistically, intracellular TLR9 was found essential to the activation of the IL-12p40 response. Blocking TLR9 signaling with CpG-ODN antagonist ameliorated IL-12p40 response, brainstem inflammation, and limb paralysis in mice with EV71-induced encephalitis. We further found the glial IL-12p40 response might damage neurons by inducing excess production of neurotoxic NO by iNOS. Overall, EV71 engagement with intracellular TLR9 was found to elicit a neurotoxic glial response via IL12p40-iNOS signaling contributing to the neurological manifestation of EV71 infection. This pathway could potentially be targeted for the treatment of brainstem encephalitis.Subject terms: Toll-like receptors, Viral infection     

Predicting drug polypharmacology from cell morphology readouts using variational autoencoder latent space arithmetic

A variational autoencoder (VAE) is a machine learning algorithm, useful for generating a compressed and interpretable latent space. These representations have been generated from various biomedical data types and can be used to produce realistic-looking simulated data. However, standard vanilla VAEs suffer from entangled and uninformative latent spaces, which can be mitigated using other types of VAEs such as β-VAE and MMD-VAE. In this project, we evaluated the ability of VAEs to learn cell morphology characteristics derived from cell images. We trained and evaluated these three VAE variants—Vanilla VAE, β-VAE, and MMD-VAE—on cell morphology readouts and explored the generative capacity of each model to predict compound polypharmacology (the interactions of a drug with more than one target) using an approach called latent space arithmetic (LSA). To test the generalizability of the strategy, we also trained these VAEs using gene expression data of the same compound perturbations and found that gene expression provides complementary information. We found that the β-VAE and MMD-VAE disentangle morphology signals and reveal a more interpretable latent space. We reliably simulated morphology and gene expression readouts from certain compounds thereby predicting cell states perturbed with compounds of known polypharmacology. Inferring cell state for specific drug mechanisms could aid researchers in developing and identifying targeted therapeutics and categorizing off-target effects in the future.