Cell Reports
All content is freely available to readers and supported through open access

Apr 07, 2020

Volume 31Issue 1
Open Access
On the cover: The cover represents a chicken that is a bilateral sex chimera (gynandromorph) as the combination of single cells with specific sexual identity. This rare organism was the key to defining the cell autonomous sex identity of the gonadal supporting lineages. Estermann et al. describe chicken embryonic gonadal development at single cell resolution, a novel technology that will be useful to understand how sex determination works in these rare cases. Image by Martin Estermann....
On the cover: The cover represents a chicken that is a bilateral sex chimera (gynandromorph) as the combination of single cells with specific sexual identity. This rare organism was the key to defining the cell autonomous sex identity of the gonadal supporting lineages. Estermann et al. describe chicken embryonic gonadal development at single cell resolution, a novel technology that will be useful to understand how sex determination works in these rare cases. Image by Martin Estermann.



  • Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis

    • Christian M. Cohrs,
    • Julia K. Panzer,
    • Denise M. Drotar,
    • Stephen J. Enos,
    • Nicole Kipke,
    • Chunguang Chen,
    • Robert Bozsak,
    • Eyke Schöniger,
    • Florian Ehehalt,
    • Marius Distler,
    • Ana Brennand,
    • Stefan R. Bornstein,
    • Jürgen Weitz,
    • Michele Solimena,
    • Stephan Speier
    Cohrs et al. utilize pancreas tissue slices of metabolically phenotyped subjects undergoing pancreatectomy to assess β cell pathogenesis in type 2 diabetes development. They reveal β cell dysfunction as an early hallmark in type 2 diabetes pathogenesis, manifesting as increased basal and missing first-phase insulin secretion, although β cell mass is maintained.
  • Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells

    • Alexandros P. Drainas,
    • Ruxandra A. Lambuta,
    • Irina Ivanova,
    • Özdemirhan Serçin,
    • Ioannis Sarropoulos,
    • Mike L. Smith,
    • Theocharis Efthymiopoulos,
    • Benjamin Raeder,
    • Adrian M. Stütz,
    • Sebastian M. Waszak,
    • Balca R. Mardin,
    • Jan O. Korbel
    Drainas et al. show that inactivation of genes in the neddylation pathway increases persistent proliferation in TP53-deficient cells. TP53- and CUL3-deficient cells induce an oncogenic transcriptional program, leading to partial EMT and heightened genomic instability. These cells show increased vulnerability to ATM inhibitors.
  • A Modular Differentiation System Maps Multiple Human Kidney Lineages from Pluripotent Stem Cells

    • Hiraku Tsujimoto,
    • Tomoko Kasahara,
    • Shin-ichi Sueta,
    • Toshikazu Araoka,
    • Satoko Sakamoto,
    • Chihiro Okada,
    • Shin-ichi Mae,
    • Taiki Nakajima,
    • Natsumi Okamoto,
    • Daisuke Taura,
    • Makoto Nasu,
    • Tatsuya Shimizu,
    • Makoto Ryosaka,
    • Zhongwei Li,
    • Masakatsu Sone,
    • Makoto Ikeya,
    • Akira Watanabe,
    • Kenji Osafune
    Tsujimoto et al. establish a differentiation system that separately generates multiple mesoderm lineages from hiPSCs. Three kidney progenitors, metanephric nephron progenitors (NPs), mesonephric NP-like cells, and the ureteric bud (UB), are further induced. They also generate interconnected kidney organoids from separately induced metanephric NPs and UB.
  • Dynamics of uS19 C-Terminal Tail during the Translation Elongation Cycle in Human Ribosomes

    • Varun Bhaskar,
    • Alexandra Graff-Meyer,
    • Andreas D. Schenk,
    • Simone Cavadini,
    • Ottilie von Loeffelholz,
    • S. Kundhavai Natchiar,
    • Caroline G. Artus-Revel,
    • Hans-Rudolf Hotz,
    • Gabriel Bretones,
    • Bruno P. Klaholz,
    • Jeffrey A. Chao
    In this study, Bhaskar et al. visualize the dynamic rearrangement of the uS19 C-terminal tail during translation elongation and elucidate its role in stabilizing aminoacyl tRNA and decoding interactions and in coordination of peptidyl tRNA movements within the mammalian ribosome during protein synthesis.


  • Plasma Cell Fate Is Orchestrated by Elaborate Changes in Genome Compartmentalization and Inter-chromosomal Hubs

    • Alexandra Bortnick,
    • Zhaoren He,
    • Megan Aubrey,
    • Vivek Chandra,
    • Matthew Denholtz,
    • Kenian Chen,
    • Yin C. Lin,
    • Cornelis Murre
    Bortnick et al. demonstrate that plasma cell fate is associated with changes in chromatin folding, inter-chromosomal interactions, and nuclear localization involving plasma-cell-specific genes. Inter-chromosomal hubs in maturing B cells are enriched for the deposition of either H3K27Ac or H3K27me3. We propose that deposition of these marks facilitates inter-chromosomal interactions.
  • T Cell Factor 1 Suppresses CD103+ Lung Tissue-Resident Memory T Cell Development

    • Jingxia Wu,
    • Alaa Madi,
    • Alessa Mieg,
    • Agnes Hotz-Wagenblatt,
    • Nina Weisshaar,
    • Sicong Ma,
    • Kerstin Mohr,
    • Tilo Schlimbach,
    • Marvin Hering,
    • Helena Borgers,
    • Guoliang Cui
    Tcf1 promotes circulating memory T cell development and maintenance after systemic infections. Wu et al. show that Tcf1 inhibits CD103+ resident memory T cell development in influenza-virus-infected mice. Tcf1 may either promote or suppress memory T cell development, depending on systemic or mucosal infections.
  • A Two-Cell Model for IL-1β Release Mediated by Death-Receptor Signaling

    • Carlos A. Donado,
    • Anh B. Cao,
    • Daimon P. Simmons,
    • Ben A. Croker,
    • Patrick J. Brennan,
    • Michael B. Brenner
    How the immune system triggers IL-1β release during infection with inflammasome-evasive microbes is largely unknown. Donado et al. describe an alternative, caspase-8-dependent IL-1β secretion pathway where a second cell, the invariant natural killer T (iNKT) cell, can provide antigen-presenting cells with cell-extrinsic IL-1β release signals through FasL.
  • TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

    • Katherine R. Balka,
    • Cynthia Louis,
    • Tahnee L. Saunders,
    • Amber M. Smith,
    • Dale J. Calleja,
    • Damian B. D’Silva,
    • Fiona Moghaddas,
    • Maximilien Tailler,
    • Kate E. Lawlor,
    • Yifan Zhan,
    • Christopher J. Burns,
    • Ian P. Wicks,
    • Jonathan J. Miner,
    • Benjamin T. Kile,
    • Seth L. Masters,
    • Dominic De Nardo
    Activation of NF-κB via STING is considered to be exclusively dependent on TBK1. Balka et al. now show that, although TBK1 and its kinase activity are critical for IRF3 activation and type I IFNs, it is dispensable for NF-κB. Instead, TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses.
  • Differentiation Paths of Peyer’s Patch LysoDCs Are Linked to Sampling Site Positioning, Migration, and T Cell Priming

    • Camille Wagner,
    • Johnny Bonnardel,
    • Clément Da Silva,
    • Lionel Spinelli,
    • Cynthia Arroyo Portilla,
    • Julie Tomas,
    • Margaux Lagier,
    • Lionel Chasson,
    • Marion Masse,
    • Marc Dalod,
    • Alexandre Chollat-Namy,
    • Jean-Pierre Gorvel,
    • Hugues Lelouard
    Wagner et al. dissect the differentiation pathways of the Peyer’s patch monocyte-derived dendritic cells termed LysoDCs. They show that LysoDCs mature as they get closer to the epithelium. Mature LysoDCs migrate to the periphery of the T cell zone, where proliferation of immune cells occurs only when stimulated.
  • Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis

    • Amy I. Yu,
    • Lili Zhao,
    • Kathryn A. Eaton,
    • Sharon Ho,
    • Jiachen Chen,
    • Sara Poe,
    • James Becker,
    • Allison Gonzalez,
    • Delaney McKinstry,
    • Muneer Hasso,
    • Jonny Mendoza-Castrejon,
    • Joel Whitfield,
    • Charles Koumpouras,
    • Patrick D. Schloss,
    • Eric C. Martens,
    • Grace Y. Chen
    The gut microbiome is capable of modulating intestinal inflammation and tumorigenesis. Yu et al. demonstrate that dysbiosis can lead to increased susceptibility to inflammation-associated colon tumorigenesis via the induction of pro-inflammatory CD8+ IFNγ+ T cells, which can lead to increased T cell exhaustion within the tumor microenvironment.
  • TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4+ T Cells to Treg

    • Joseph S. Dolina,
    • Joey Lee,
    • Ryan Q. Griswold,
    • Lara Labarta-Bajo,
    • Sumetha Kannan,
    • Jason A. Greenbaum,
    • Nawal Bahia El Idrissi,
    • Margot J. Pont,
    • Michael Croft,
    • Stephen P. Schoenberger
    Dolina et al. show that Listeria infectious dose drives conventional CD4+ T cells to act as TH or mediates conversion to Treg. Differentiation to Treg dominates heightened doses and is promoted by CD8α+ DC TLR9 engagement of neutrophil self-DNA and IL-12 production, revealing plasticity in the function of CD4+ T cells.
  • Structure of Super-Potent Antibody CAP256-VRC26.25 in Complex with HIV-1 Envelope Reveals a Combined Mode of Trimer-Apex Recognition

    • Jason Gorman,
    • Gwo-Yu Chuang,
    • Yen-Ting Lai,
    • Chen-Hsiang Shen,
    • Jeffrey C. Boyington,
    • Aliaksandr Druz,
    • Hui Geng,
    • Mark K. Louder,
    • Krisha McKee,
    • Reda Rawi,
    • Raffaello Verardi,
    • Yongping Yang,
    • Baoshan Zhang,
    • Nicole A. Doria-Rose,
    • Bob Lin,
    • Penny L. Moore,
    • Lynn Morris,
    • Lawrence Shapiro,
    • John R. Mascola,
    • Peter D. Kwong
    Antibody CAP256-VRC26.25 is one of the most potent known HIV-1-neutralizing antibodies. Gorman et al. determine the cryo-EM structure of this antibody in complex with the Env trimer that initiated the antibody lineage. The structure reveals how elements of distinct antibody classes can intermingle to yield an antibody of extraordinary potency.
  • Passenger Mutations Confound Phenotypes of SARM1-Deficient Mice

    • Melissa B. Uccellini,
    • Susana V. Bardina,
    • Maria Teresa Sánchez-Aparicio,
    • Kris M. White,
    • Ying-Ju Hou,
    • Jean K. Lim,
    • Adolfo García-Sastre
    Existing C57BL/6J Sarm1−/− mouse lines were made on the 129 background, and genes surrounding the knockout locus remain 129 in sequence. Uccellini et al. show that CRISPR mouse lines retain decreased axonal degeneration and increased WNV susceptibility, but not VSV or LACV viral phenotypes or chemokine or Xaf1 expression phenotypes.
  • Innate Immunity in the C. elegans Intestine Is Programmed by a Neuronal Regulator of AWC Olfactory Neuron Development

    • Kyle J. Foster,
    • Hilary K. Cheesman,
    • Pengpeng Liu,
    • Nicholas D. Peterson,
    • Sarah M. Anderson,
    • Read Pukkila-Worley
    During nematode development, the olfactory neuron gene olrn-1 programs odorant receptor expression in AWC neurons. Foster et al. show that olrn-1 also functions in AWC neurons to suppress innate immune defenses in the intestine. These data reveal an unexpected connection between olfactory receptor development and innate immunity.
  • Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch

    • Santosh K. Mishra,
    • Joshua J. Wheeler,
    • Saumitra Pitake,
    • Huiping Ding,
    • Changyu Jiang,
    • Tomoki Fukuyama,
    • Judy S. Paps,
    • Patrick Ralph,
    • Jacob Coyne,
    • Michelle Parkington,
    • Jennifer DeBrecht,
    • Lauren C. Ehrhardt-Humbert,
    • Glenn P. Cruse,
    • Wolfgang Bäumer,
    • Ru-Rong Ji,
    • Mei-Chuan Ko,
    • Thierry Olivry
    Mishra et al. demonstrate periostin-induced itch in mice, dogs, and monkeys and identify the integrin αVβ3 as the periostin neuronal receptor. They find that keratinocytes release periostin in response to TSLP, thus identifying a possible reciprocal vicious circle implicating the cytokine TSLP and periostin in chronic allergic itch.
  • Visual Experience-Dependent Oscillations and Underlying Circuit Connectivity Changes Are Impaired in Fmr1 KO Mice

    • Samuel T. Kissinger,
    • Qiuyu Wu,
    • Christopher J. Quinn,
    • Adam K. Anderson,
    • Alexandr Pak,
    • Alexander A. Chubykin
    Kissinger et al. study perceptual experience-dependent visual cortical oscillations in Fragile X mice using extracellular electrophysiology, revealing decreased oscillatory magnitudes and altered temporal profiles in Fragile X mice. Additionally, they perform a cross-layer functional connectivity analysis of these data and channelrhodopsin-2 assisted circuit mapping to identify underlying circuit differences.
  • Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma

    • Nathan A. Dahl,
    • Etienne Danis,
    • Ilango Balakrishnan,
    • Dong Wang,
    • Angela Pierce,
    • Faye M. Walker,
    • Ahmed Gilani,
    • Natalie J. Serkova,
    • Krishna Madhavan,
    • Susan Fosmire,
    • Adam L. Green,
    • Nicholas K. Foreman,
    • Sujatha Venkataraman,
    • Rajeev Vibhakar
    Dahl et al. use a targeted RNAi screen to identify the SEC as a dependency in diffuse midline glioma. SEC-mediated signaling promotes clonogenic potential and self-renewal of tumor stem cells. Pharmacologic inhibition of SEC restores regulatory RNA Pol II pausing, promotes cellular differentiation, and prolongs survival in patient-derived xenograft models.
  • Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma

    • Haider M. Hassan,
    • Majdina Isovic,
    • Bart Kolendowski,
    • Natasha Bauer-Maison,
    • Oladapo Onabote,
    • Matthew Cecchini,
    • Aaron Haig,
    • Saman Maleki Vareki,
    • T. Michael Underhill,
    • Joseph Torchia
    TDG is a base excision repair protein that is essential for embryonic development. Hassan et al. show that the conditional deletion of TDG in adult mice causes dysregulation of FXR signaling and a loss of glucose and bile acid homeostasis. This leads to a late-onset development of hepatocellular carcinoma.
  • FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression

    • Mayumi Hirayama,
    • Fan-Yan Wei,
    • Takeshi Chujo,
    • Shinya Oki,
    • Maya Yakita,
    • Daiki Kobayashi,
    • Norie Araki,
    • Nozomu Takahashi,
    • Ryoji Yoshida,
    • Hideki Nakayama,
    • Kazuhito Tomizawa
    Hirayama et al. show that FTO, the demethylase for m6A modification, regulates G1 cell-cycle progression by targeting cyclin D1 mRNA. Their studies indicate that m6A modification of mRNA can be periodically regulated during the cell cycle and that m6A demethylase FTO may be a therapeutic target for cancer treatment.
  • Precise Tuning of Cortical Contractility Regulates Cell Shape during Cytokinesis

    • Nilay Taneja,
    • Matthew R. Bersi,
    • Sophie M. Baillargeon,
    • Aidan M. Fenix,
    • James A. Cooper,
    • Ryoma Ohi,
    • Vivian Gama,
    • W. David Merryman,
    • Dylan T. Burnette
    Taneja et al. describe distinct roles for the two myosin-II paralogs in regulating actin cortex mechanics during cell division. Myosin-IIA generates cortex tension, while myosin-IIB maintains cortical stability. Optimal levels of the two paralogs within hetero-filaments at the cortex are required for shape stability and cytokinetic fidelity during cell division.
  • Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity

    • Kazunori Sasaki,
    • Noriko Kojitani,
    • Hiroko Hirose,
    • Yohei Yoshihama,
    • Hidefumi Suzuki,
    • Miho Shimada,
    • Ayumi Takayanagi,
    • Akio Yamashita,
    • Masa-aki Nakaya,
    • Hisashi Hirano,
    • Hidehisa Takahashi,
    • Shigeo Ohno
    Sasaki et al. demonstrate that epithelial Shank2 localizes at tight junctions (TJs) via its epithelia-specific N terminus and interacts with aPKC. Through small GTPase Rap1 signaling, the aPKC-Shank2 complex functions as a platform for TJ assembly during the establishment of the epithelial cell polarity.
  • Integration of Nodal and BMP Signaling by Mutual Signaling Effector Antagonism

    • Gary Huiming Soh,
    • Autumn Penecilla Pomreinke,
    • Patrick Müller
    Juxtaposed Nodal and BMP sources can induce the formation of a secondary axis in zebrafish embryos. Soh et al. analyze the input-output relationships in this patterning system and find that differential signaling kinetics lead to different activity ranges of Nodal and BMP, which are crucial for secondary axis formation.
  • Structural Insights into the Mammalian Late-Stage Initiation Complexes

    • Angelita Simonetti,
    • Ewelina Guca,
    • Anthony Bochler,
    • Lauriane Kuhn,
    • Yaser Hashem
    Simonetti et al. present a high-resolution snapshot of the architecture of mammalian late-stage translation initiation complexes prepared in near native conditions. They provide structural insights into the Kozak sequence interactions of two different archetype mRNA sequences with the ribosome during translation initiation.
  • PGC1α Controls Sucrose Taste Sensitization in Drosophila

    • Qiao-Ping Wang,
    • Yong Qi Lin,
    • Mei-Ling Lai,
    • Zhiduan Su,
    • Lisa J. Oyston,
    • Teleri Clark,
    • Scarlet J. Park,
    • Thang M. Khuong,
    • Man-Tat Lau,
    • Victoria Shenton,
    • Yan-Chuan Shi,
    • David E. James,
    • William W. Ja,
    • Herbert Herzog,
    • Stephen J. Simpson,
    • G. Gregory Neely
    Wang et al. show that manipulation of diet composition can alter subsequent sweet taste sensitivity. This effect involves dopamine signaling pathways and PGC1α. These findings explain how diet composition can impact future sweet taste perception.
  • Insights into Gonadal Sex Differentiation Provided by Single-Cell Transcriptomics in the Chicken Embryo

    • Martin Andres Estermann,
    • Sarah Williams,
    • Claire Elizabeth Hirst,
    • Zahida Yesmin Roly,
    • Olivier Serralbo,
    • Deepak Adhikari,
    • David Powell,
    • Andrew Thomas Major,
    • Craig Allen Smith
    Gonadal cell-lineage specification during embryogenesis has long been thought to be similar among vertebrates. In this chicken study, Estermann et al. show that this is not the case, finding major differences between mouse and chicken. This study provides evolutionary insights into gonadal sex differentiation.


  • Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex

    • Donna M. Werling,
    • Sirisha Pochareddy,
    • Jinmyung Choi,
    • Joon-Yong An,
    • Brooke Sheppard,
    • Minshi Peng,
    • Zhen Li,
    • Claudia Dastmalchi,
    • Gabriel Santpere,
    • André M.M. Sousa,
    • Andrew T.N. Tebbenkamp,
    • Navjot Kaur,
    • Forrest O. Gulden,
    • Michael S. Breen,
    • Lindsay Liang,
    • Michael C. Gilson,
    • Xuefang Zhao,
    • Shan Dong,
    • Lambertus Klei,
    • A. Ercument Cicek,
    • Joseph D. Buxbaum,
    • Homa Adle-Biassette,
    • Jean-Leon Thomas,
    • Kimberly A. Aldinger,
    • Diana R. O’Day,
    • Ian A. Glass,
    • Noah A. Zaitlen,
    • Michael E. Talkowski,
    • Kathryn Roeder,
    • Matthew W. State,
    • Bernie Devlin,
    • Stephan J. Sanders,
    • Nenad Sestan
    Werling et al. analyze gene expression across the span of human cerebral cortical development and profile the trajectories of individual genes, coordinated groups of genes, and their relationships to disorders. Integration of genetic variation identifies quantitative trait loci that implicate specific genes in loci associated with neuropsychiatric traits and disorders.
  • Gene Regulatory and Expression Differences between Mouse and Pig Limb Buds Provide Insights into the Evolutionary Emergence of Artiodactyl Traits

    • Virginie Tissières,
    • Florian Geier,
    • Barbara Kessler,
    • Eckhard Wolf,
    • Rolf Zeller,
    • Javier Lopez-Rios
    Tissières et al. show that, in comparison to the pentadactyl mouse limb, the expression and regulation of key developmental pathways are altered during pig limb bud development. These changes likely contributed to the morphological evolution of the highly specialized pig limb skeleton, with two weight-bearing and two reduced digits.
  • A Targeted Multi-omic Analysis Approach Measures Protein Expression and Low-Abundance Transcripts on the Single-Cell Level

    • Florian Mair,
    • Jami R. Erickson,
    • Valentin Voillet,
    • Yannick Simoni,
    • Timothy Bi,
    • Aaron J. Tyznik,
    • Jody Martin,
    • Raphael Gottardo,
    • Evan W. Newell,
    • Martin Prlic
    Mair et al. describe a targeted transcriptomics approach combined with surface protein measurement to capture immune cell heterogeneity at a low sequencing depth. One-SENSE is used as a visualization tool to intuitively explore the relationship of protein and transcript expression on the single-cell level.