Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine

In the development of the mammalian intestine, Notch and Wnt/{beta}-catenin signals control stem cell maintenance and their differentiation into absorptive and secretory cells. Mechanisms that regulate differentiation of progenitors into the three secretory lineages, goblet, paneth, or enteroendocrine cells, are not fully understood. Using conditional mutagenesis in mice, we observed that Shp2-mediated MAPK signaling determines the choice between paneth and goblet cell fates and also affects stem cells, which express the leucine-rich repeat-containing receptor 5 (Lgr5). Ablation of the tyrosine phosphatase Shp2 in the intestinal epithelium reduced MAPK signaling and led to a reduction of goblet cells while promoting paneth cell development. Conversely, conditional mitogen-activated protein kinase kinase 1 (Mek1) activation rescued the Shp2 phenotype, promoted goblet cell and inhibited paneth cell generation. The Shp2 mutation also expanded Lgr5+ stem cell niches, which could be restricted by activated Mek1 signaling. Changes of Lgr5+ stem cell quantities were accompanied by alterations of paneth cells, indicating that Shp2/MAPK signaling might affect stem cell niches directly or via paneth cells. Remarkably, inhibition of MAPK signaling in intestinal organoids and cultured cells changed the relative abundance of Tcf4 isoforms and by this, promoted Wnt/{beta}-catenin activity. The data thus show that Shp2-mediated MAPK signaling controls the choice between goblet and paneth cell fates by regulating Wnt/{beta}-catenin activity

A transcription factor code defines nine sensory interneuron subtypes in the mechanosensory area of the spinal cord

Interneurons in the dorsal spinal cord process and relay innocuous and nociceptive somatosensory information from cutaneous receptors that sense touch, temperature and pain. These neurons display a well-defined organization with respect to their afferent innervation. Nociceptive afferents innervate lamina I and II, while cutaneous mechanosensory afferents primarily innervate sensory interneurons that are located in lamina III-IV. In this study, we outline a combinatorial transcription factor code that defines nine different inhibitory and excitatory interneuron populations in laminae III-IV of the postnatal cord. This transcription factor code reveals a high degree of molecular diversity in the neurons that make up laminae III-IV, and it lays the foundation for systematically analyzing and manipulating these different neuronal populations to assess their function. In addition, we find that many of the transcription factors that are expressed in the dorsal spinal cord at early postnatal times continue to be expressed in the adult, raising questions about their function in mature neurons and opening the door to their genetic manipulation in adult animals

Tyrosine kinase receptor RON functions downstream of the erythropoietin

Erythropoietin (EPO) is required for cell survival during differentiation and for progenitor expansion during stress erythropoiesis. Although signaling pathways may couple directly to docking sites on the EPO receptor (EpoR), additional docking molecules expand the signaling platform of the receptor. We studied the roles of the docking molecules Grb2-associated binder-1 (Gab1) and Gab2 in EPO-induced signal transduction and erythropoiesis. Inhibitors of phosphatidylinositide 3-kinase and Src kinases suppressed EPO-dependent phosphorylation of Gab2. In contrast, Gab1 activation depends on recruitment and phosphorylation by the tyrosine kinase receptor RON, with which it is constitutively associated. RON activation induces the phosphorylation of Gab1, mitogen-activated protein kinase (MAPK), and protein kinase B (PKB) but not of signal transducer and activator of transcription 5 (Stat5). RON activation was sufficient to replace EPO in progenitor expansion but not in differentiation. In conclusion, we elucidated a novel mechanism specifically involved in the expansion of erythroblasts involving RON as a downstream target of the Epo

Search for heavy resonances decaying to a top quark and a bottom quark in the lepton+jets final state in proton–proton collisions at 13 TeV

A search is presented for narrow heavy resonances decaying to a top quark and a bottom quark using data collected by the CMS experiment at √s = 13TeV in 2016. The data set analyzed corresponds to an integrated luminosity of 35.9 fb−1. Final states that include a single lepton (e, μ), multiple jets, and missing transverse momentum are analyzed. No evidence is found for the production of a W′ boson, and the production of right-handed W′ bosons is excluded at 95% confidence level for masses up to 3.6 TeV depending on the scenario considered. Exclusion limits for W′ bosons are also presented as a function of their coupling strength to left- and right-handed fermions. These limits on a W′ boson decaying via a top and a bottom quark are the most stringent published to date

Measurement of angular parameters from the decay B⁰ → K⁎0^{⁎0} μ⁺ μ⁻ in proton–proton collisions at √s 8 TeV

Angular distributions of the decay B⁰  → K$^{⁎0}$ μ⁺ μ⁻ are studied using a sample of proton–proton collisions at √s=8TeV collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 20.5fb⁻¹ . An angular analysis is performed to determine the P₁ and P$^{\u27}$₅ parameters, where the P$^{\u27}$₅ parameter is of particular interest because of recent measurements that indicate a potential discrepancy with the standard model predictions. Based on a sample of 1397 signal events, the P₁ and P$^{\u27}$₅ parameters are determined as a function of the dimuon invariant mass squared. The measurements are in agreement with predictions based on the standard model

Nuclear modification factor of D0 mesons in PbPb collisions at sNN=5.02TeV

The transverse momentum (pT) spectrum of prompt D0 mesons and their antiparticles has been measured via the hadronic decay channels D0→K−π+ and D‾0→K+π− in pp and PbPb collisions at a centre-of-mass energy of 5.02 TeV per nucleon pair with the CMS detector at the LHC. The measurement is performed in the D0 meson pT range of 2–100GeV/c and in the rapidity range of |y|<1. The pp (PbPb) dataset used for this analysis corresponds to an integrated luminosity of 27.4 pb−1 (530 μb−1). The measured D0 meson pT spectrum in pp collisions is well described by perturbative QCD calculations. The nuclear modification factor, comparing D0 meson yields in PbPb and pp collisions, was extracted for both minimum-bias and the 10% most central PbPb interactions. For central events, the D0 meson yield in the PbPb collisions is suppressed by a factor of 5–6 compared to the pp reference in the pT range of 6–10GeV/c. For D0 mesons in the high-pT range of 60–100GeV/c, a significantly smaller suppression is observed. The results are also compared to theoretical calculations

Search for single production of a vector-like T quark decaying to a Z boson and a top quark in proton–proton collisions at √s = 13 TeV

A search is presented for single production of a vector-like quark (T) decaying to a Z boson and a top quark, with the Z boson decaying leptonically and the top quark decaying hadronically. The search uses data collected by the CMS experiment in proton–proton collisions at a center-of-mass energy of 13 TeV in 2016, corresponding to an integrated luminosity of 35.9 fb⁻¹. The presence of forward jets is a particular characteristic of single production of vector-like quarks that is used in the analysis. For the first time, different T quark width hypotheses are studied, from negligibly small to 30% of the new particle mass. At the 95% confidence level, the product of cross section and branching fraction is excluded above values in the range 0.26–0.04 pb for T quark masses in the range 0.7–1.7 TeV, assuming a negligible width. A similar sensitivity is observed for widths of up to 30% of the T quark mass. The production of a heavy Z′ boson decaying to Tt, with T→tZ, is also searched for, and limits on the product of cross section and branching fractions for this process are set between 0.13 and 0.06 pb for Z′ boson masses in the range from 1.5 to 2.5 TeV