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1.
Nat Immunol ; 20(3): 374, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30733606

ABSTRACT

In the version of this article initially published, the Supplementary Data file was an incorrect version. The correct version is now provided. The error has been corrected in the HTML and PDF version of the article.

2.
Nat Immunol ; 19(5): 497-507, 2018 05.
Article in English | MEDLINE | ID: mdl-29662170

ABSTRACT

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell-mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Gene Expression Regulation/immunology , Gene Regulatory Networks/immunology , Interleukin-2/biosynthesis , Proto-Oncogene Proteins c-maf/immunology , Animals , Interleukin-2/immunology , Mice
3.
Science ; 356(6339): 722-726, 2017 05 19.
Article in English | MEDLINE | ID: mdl-28522527

ABSTRACT

The enteric nervous system (ENS) is essential for digestive function and gut homeostasis. Here we show that the amorphous neuroglia networks of the mouse ENS are composed of overlapping clonal units founded by postmigratory neural crest-derived progenitors. The spatial configuration of ENS clones depends on proliferation-driven local interactions of ENS progenitors with lineally unrelated neuroectodermal cells, the ordered colonization of the serosa-mucosa axis by clonal descendants, and gut expansion. Single-cell transcriptomics and mutagenesis analysis delineated dynamic molecular states of ENS progenitors and identified RET as a regulator of neurogenic commitment. Clonally related enteric neurons exhibit synchronous activity in response to network stimulation. Thus, lineage relationships underpin the organization of the peripheral nervous system.


Subject(s)
Cell Lineage , Enteric Nervous System/cytology , Animals , Cell Lineage/genetics , Cell Proliferation , Clone Cells/cytology , Enteric Nervous System/metabolism , Intestinal Mucosa/cytology , Mice , Mosaicism , Mutagenesis , Neural Crest/cytology , Neurogenesis , Neuroglia/physiology , Neurons/cytology , Sequence Analysis, RNA , Signal Transduction , Single-Cell Analysis , Stem Cells/cytology , Transcriptome
4.
Dev Cell ; 40(3): 289-301.e3, 2017 02 06.
Article in English | MEDLINE | ID: mdl-28132849

ABSTRACT

Somatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a "sex-reversed" X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility.


Subject(s)
Chromosomes, Human, X/genetics , Dosage Compensation, Genetic , Germ Cells/metabolism , Sex Characteristics , X Chromosome/genetics , Animals , Cellular Reprogramming/genetics , Databases, Genetic , Female , Gene Expression Profiling , Gene Expression Regulation , Germ Cells/cytology , Gonads/cytology , Gonads/metabolism , Humans , Male , Mice , Models, Genetic , Sequence Analysis, RNA , Up-Regulation/genetics
5.
Cancer Cell ; 32(3): 324-341.e6, 2017 09 11.
Article in English | MEDLINE | ID: mdl-28870739

ABSTRACT

The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.


Subject(s)
Antineoplastic Agents/therapeutic use , Bone Marrow/pathology , Capillary Permeability , Cellular Microenvironment , Disease Progression , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Animals , Antineoplastic Agents/pharmacology , Bone Marrow/drug effects , Capillary Permeability/drug effects , Cellular Microenvironment/drug effects , Gene Expression Profiling , Gene Expression Regulation, Leukemic/drug effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Neoplasm Transplantation/pathology , Nitric Oxide/metabolism , Treatment Outcome
6.
Nat Cell Biol ; 18(12): 1346-1356, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27798604

ABSTRACT

The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. Here we show that Lgr6 marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lineage tracing analysis showed that Lgr6+ cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. In pregnancy or following stimulation with ovarian hormones, adult Lgr6+ cells regained proliferative potency and their progeny formed alveoli over repeated pregnancies. Oncogenic mutations in Lgr6+ cells resulted in expansion of luminal cells, culminating in mammary gland tumours. Conversely, depletion of Lgr6+ cells in the MMTV-PyMT model of mammary tumorigenesis significantly impaired tumour growth. Thus, Lgr6 marks mammary gland progenitor cells that can initiate tumours, and cells of luminal breast tumours required for efficient tumour maintenance.


Subject(s)
Breast Neoplasms/pathology , Mammary Glands, Animal/pathology , Mammary Neoplasms, Experimental/pathology , Receptors, G-Protein-Coupled/metabolism , Stem Cells/pathology , Alleles , Animals , Animals, Newborn , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Carcinogenesis/pathology , Cell Lineage , Cell Proliferation , Clone Cells , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Homeostasis , Hormones/pharmacology , Humans , Mammary Glands, Animal/growth & development , Mammary Neoplasms, Experimental/genetics , Mice , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Pregnancy , Stem Cells/metabolism , Up-Regulation
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