55 research outputs found
Cell Host Microbe
No full textAltered commensal communities are associated with human disease. IgA mediates intestinal homeostasis and regulates microbiota composition. Intestinal IgA is produced at high levels as a result of T follicular helper cell (TFH) and B cell interactions in germinal centers. However, the pathways directing host IgA responses toward the microbiota remain unknown. Here, we report that signaling through the innate adaptor MyD88 in gut T\ua0cells coordinates germinal center responses, including TFH and IgA+ B cell development. TFH development is deficient in germ-free mice and can be restored by feeding TLR2 agonists that activate T\ua0cell-intrinsic MyD88 signaling. Loss of this pathway diminishes high-affinity IgA targeting of the microbiota and fails to control the bacterial community, leading to worsened disease. Our findings identify that T\ua0cells converge innate and adaptive immune signals to coordinate IgA against the microbiota, constraining microbial community membership to promote symbiosis.1S10RR026802-01/RR/NCRR NIH HHS/United States5-P39-DK034987/DK/NIDDK NIH HHS/United States5-P40-OD010995/OD/NIH HHS/United StatesAI107090/AI/NIAID NIH HHS/United StatesAI109122/AI/NIAID NIH HHS/United StatesDP2 AT008746/AT/NCCIH NIH HHS/United StatesDP2AT008746-01/AT/NCCIH NIH HHS/United StatesDP2GM111099-01/DP/NCCDPHP CDC HHS/United StatesK22 AI095375/AI/NIAID NIH HHS/United StatesK22 AI95375/AI/NIAID NIH HHS/United StatesP30 DK034987/DK/NIDDK NIH HHS/United StatesP40 OD010995/OD/NIH HHS/United StatesR00HL102228-05/HL/NHLBI NIH HHS/United StatesR21 AI109122/AI/NIAID NIH HHS/United StatesT32 AI-055434/AI/NIAID NIH HHS/United StatesT32 GM007464/GM/NIGMS NIH HHS/United State
IgA Targets the Troublemakers
No full textResident microbes within the gastrointestinal tract are known to influence the progression of inflammatory bowel diseases (IBD); however, the identity of the bacteria that exacerbate inflammation remains unknown. In the most recent issue of Cell, Palm et al. (2014) utilize the host immune response as a way to identify colitogenic bacteria
PLoS One
No full textMammalian microRNA expression is dysregulated in human cancer. However, the functional relevance of many microRNAs in the context of tumor biology remains unclear. Using CRISPR-Cas9 technology, we performed a global loss-of-function screen to simultaneously test the functions of individual microRNAs and protein-coding genes during the growth of a myeloid leukemia cell line. This approach identified evolutionarily conserved human microRNAs that suppress or promote cell growth, revealing that microRNAs are extensively integrated into the molecular networks that control tumor cell physiology. miR-155 was identified as a top microRNA candidate promoting cellular fitness, which we confirmed with two distinct miR-155-targeting CRISPR-Cas9 lentiviral constructs. Further, we performed anti-correlation functional profiling to predict relevant microRNA-tumor suppressor gene or microRNA-oncogene interactions in these cells. This analysis identified miR-150 targeting of p53, a connection that was experimentally validated. Taken together, our study describes a powerful genetic approach by which the function of individual microRNAs can be assessed on a global level, and its use will rapidly advance our understanding of how microRNAs contribute to human disease.20165P30CA042014-24/CA/NCI NIH HHS/United StatesDP2GM111099-01/DP/NCCDPHP CDC HHS/United States27081855PMC48334281018
Nat Commun
No full textThe presentation of protein antigens on the cell surface by major histocompatibility complex (MHC) molecules coordinates vertebrate adaptive immune responses, thereby mediating susceptibility to a variety of autoimmune and infectious diseases. The composition of symbiotic microbial communities (the microbiota) is influenced by host immunity and can have a profound impact on host physiology. Here we use an MHC congenic mouse model to test the hypothesis that genetic variation at MHC genes among individuals mediates susceptibility to disease by controlling microbiota composition. We find that MHC genotype significantly influences antibody responses against commensals in the gut, and that these responses are correlated with the establishment of unique microbial communities. Transplantation experiments in germfree mice indicate that MHC-mediated differences in microbiota composition are sufficient to explain susceptibility to enteric infection. Our findings indicate that MHC polymorphisms contribute to defining an individual's unique microbial fingerprint that influences health.DP2 AT008746/AT/NCCIH NIH HHSUnited States/P40 OD010995/OD/NIH HHSUnited States/K22 AI95375/AI/NIAID NIH HHSUnited States/DP2 GM111099/GM/NIGMS NIH HHSUnited States/N01AI95375/AI/NIAID NIH HHSUnited States/R00 HL102228/HL/NHLBI NIH HHSUnited States/P30 DK034987/DK/NIDDK NIH HHSUnited States/DP2AT008746-01/AT/NCCIH NIH HHSUnited States/T32 AI-055434/AI/NIAID NIH HHSUnited States/1S10RR026802-01/RR/NCRR NIH HHSUnited States/S10 RR026802/RR/NCRR NIH HHSUnited States/5-P39-DK034987/DK/NIDDK NIH HHSUnited States/T32 AI055434/AI/NIAID NIH HHSUnited States/AI109122/AI/NIAID NIH HHSUnited States/K22 AI095375/AI/NIAID NIH HHSUnited States/DP2GM111099-01/DP/NCCDPHP CDC HHSUnited States/R56 AI107090/AI/NIAID NIH HHSUnited States/AI107090/AI/NIAID NIH HHSUnited States/T32 GM007464/GM/NIGMS NIH HHSUnited States/R21 AI109122/AI/NIAID NIH HHSUnited States/5-P40-OD010995/OD/NIH HHSUnited States/R00HL102228-05/HL/NHLBI NIH HHSUnited States
Retinoic acid is required for endodermal pouch morphogenesis and not for pharyngeal endoderm specification
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Neuronal Neuregulin 1 type III directs Schwann cell migration
No full textDuring peripheral nerve development, each segment of a myelinated axon is matched with a single Schwann cell. Tight regulation of Schwann cell movement, proliferation and differentiation is essential to ensure that these glial cells properly associate with axons. ErbB receptors are required for Schwann cell migration, but the operative ligand and its mechanism of action have remained unknown. We demonstrate that zebrafish Neuregulin 1 (Nrg1) type III, which signals through ErbB receptors, controls Schwann cell migration in addition to its previously known roles in proliferation and myelination. Chimera analyses indicate that ErbB receptors are required in all migrating Schwann cells, and that Nrg1 type III is required in neurons for migration. Surprisingly, expression of the ligand in a few axons is sufficient to induce migration along a chimeric nerve constituted largely of nrg1 type III mutant axons. These studies also reveal a mechanism that allows Schwann cells to fasciculate axons regardless of nrg1 type III expression. Time-lapse imaging of transgenic embryos demonstrated that misexpression of human NRG1 type III results in ectopic Schwann cell migration, allowing them to aberrantly enter the central nervous system. These results demonstrate that Nrg1 type III is an essential signal that controls Schwann cell migration to ensure that these glia are present in the correct numbers and positions in developing nerves.</jats:p
The composition of the zebrafish intestinal microbial community varies across development
No full textThe assembly of resident microbial communities is an important event in animal development; however, the extent to which this process mirrors the developmental programs of host tissues is unknown. Here we surveyed the intestinal bacteria at key developmental time points in a sibling group of 135 individuals of a model vertebrate, the zebrafish (Danio rerio). Our survey revealed stage-specific signatures in the intestinal microbiota and extensive interindividual variation, even within the same developmental stage. Microbial community shifts were apparent during periods of constant diet and environmental conditions, as well as in concert with dietary and environmental change. Interindividual variation in the intestinal microbiota increased with age, as did the difference between the intestinal microbiota and microbes in the surrounding environment. Our results indicate that zebrafish intestinal microbiota assemble into distinct communities throughout development, and that these communities are increasingly different from the surrounding environment and from one another
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