Cell-Cycle-Dependent ERK Signaling Dynamics Direct Fate Specification in the Mammalian Preimplantation Embryo.
Abstract Despite the noisy nature of single cells, multicellular organisms robustly generate different cell types from one zygote. This process involves dynamic cross regulation between signaling and gene expression that is difficult to capture with fixed-cell approaches. To study signaling dynamics and fate specification during preimplantation development, we generated a transgenic mouse expressing the ERK kinase translocation reporter and measured ERK activity in single cells of live embryos. Our results show primarily active ERK in both the inner cell mass and trophectoderm cells due to fibroblast growth factor...
Source: Developmental Cell - October 16, 2020 Category: Cytology Authors: Pokrass MJ, Ryan KA, Xin T, Pielstick B, Timp W, Greco V, Regot S Tags: Dev Cell Source Type: research

Live Visualization of ERK Activity in the Mouse Blastocyst Reveals Lineage-Specific Signaling Dynamics.
AK Abstract FGF/ERK signaling is crucial for the patterning and proliferation of cell lineages that comprise the mouse blastocyst. However, ERK signaling dynamics have never been directly visualized in live embryos. To address whether differential signaling is associated with particular cell fates and states, we generated a targeted mouse line expressing an ERK-kinase translocation reporter (KTR) that enables live quantification of ERK activity at single-cell resolution. 3D time-lapse imaging of this biosensor in embryos revealed spatially graded ERK activity in the trophectoderm prior to overt polar versus mural...
Source: Developmental Cell - October 16, 2020 Category: Cytology Authors: Simon CS, Rahman S, Raina D, Schröter C, Hadjantonakis AK Tags: Dev Cell Source Type: research

Phase Separation-A Physical Mechanism for Organizing Information and Biochemical Reactions.
Abstract Advances in molecular biology continue to help us uncover how information written into genes provides a blueprint for the initiation and orchestration of programs and processes that control cell division, cell-type specification, cell migration, cellular differentiation, and cell death. Clearly, molecular elements into which information is written must "talk to one another" and "work with each other" to generate appropriate cellular responses to cues and signals. PMID: 33049210 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - October 12, 2020 Category: Cytology Authors: Pappu RV Tags: Dev Cell Source Type: research

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force.
dou M Abstract Protein aggregation is the main hallmark of neurodegenerative diseases. Many proteins found in pathological inclusions are known to undergo liquid-liquid phase separation, a reversible process of molecular self-assembly. Emerging evidence supports the hypothesis that aberrant phase separation behavior may serve as a trigger of protein aggregation in neurodegeneration, and efforts to understand and control the underlying mechanisms are underway. Here, we review similarities and differences among four main proteins, α-synuclein, FUS, tau, and TDP-43, which are found aggregated in different disea...
Source: Developmental Cell - October 12, 2020 Category: Cytology Authors: Zbinden A, Pérez-Berlanga M, De Rossi P, Polymenidou M Tags: Dev Cell Source Type: research

Emerging Roles for Phase Separation in Plants.
Abstract The plant cell internal environment is a dynamic, intricate landscape composed of many intracellular compartments. Cells organize some cellular components through formation of biomolecular condensates-non-stoichiometric assemblies of protein and/or nucleic acids. In many cases, phase separation appears to either underly or contribute to the formation of biomolecular condensates. Many canonical membraneless compartments within animal cells form in a manner that is at least consistent with phase separation, including nucleoli, stress granules, Cajal bodies, and numerous additional bodies, regulated by devel...
Source: Developmental Cell - October 12, 2020 Category: Cytology Authors: Emenecker RJ, Holehouse AS, Strader LC Tags: Dev Cell Source Type: research

Biomolecular Condensates and Gene Activation in Development and Disease.
Abstract Activating the right gene at the right time and place is essential for development. Emerging evidence suggests that this process is regulated by the mesoscale compartmentalization of the gene-control machinery, RNA polymerase II and its cofactors, within biomolecular condensates. Coupling gene activity to the reversible and dynamic process of condensate formation is proposed to enable the robust and precise changes in gene-regulatory programs during signaling and development. The macromolecular features that enable condensates and the regulatory pathways that control them are dysregulated in disease, high...
Source: Developmental Cell - October 12, 2020 Category: Cytology Authors: Sabari BR Tags: Dev Cell Source Type: research

Visualizing Molecular Architectures of Cellular Condensates: Hints of Complex Coacervation Scenarios.
Abstract In the last decade, liquid-liquid phase separation has emerged as a fundamental principle in the organization of crowded cellular environments into functionally distinct membraneless compartments. It is now established that biomolecules can condense into various physical phases, traditionally defined for simple polymer systems, and more recently elucidated by techniques employed in life sciences. We review pioneering cryo-electron tomography studies that have begun to unravel a wide spectrum of molecular architectures, ranging from amorphous to crystalline assemblies, that underlie cellular condensates. T...
Source: Developmental Cell - October 12, 2020 Category: Cytology Authors: Goetz SK, Mahamid J Tags: Dev Cell Source Type: research

Hedgehog Pathway Activation Requires Coreceptor-Catalyzed, Lipid-Dependent Relay of the Sonic Hedgehog Ligand.
Abstract Hedgehog signaling governs critical processes in embryogenesis, adult stem cell maintenance, and tumorigenesis. The activating ligand, Sonic hedgehog (SHH), is highly hydrophobic because of dual palmitate and cholesterol modification, and thus, its release from cells requires the secreted SCUBE proteins. We demonstrate that the soluble SCUBE-SHH complex, although highly potent in cellular assays, cannot directly signal through the SHH receptor, Patched1 (PTCH1). Rather, signaling by SCUBE-SHH requires a molecular relay mediated by the coreceptors CDON/BOC and GAS1, which relieves SHH inhibition by SCUBE. ...
Source: Developmental Cell - October 6, 2020 Category: Cytology Authors: Wierbowski BM, Petrov K, Aravena L, Gu G, Xu Y, Salic A Tags: Dev Cell Source Type: research

Super-Resolution Microscopy and FIB-SEM Imaging Reveal Parental Centriole-Derived, Hybrid Cilium in Mammalian Multiciliated Cells.
Abstract Motile cilia are cellular beating machines that play a critical role in mucociliary clearance, cerebrospinal fluid movement, and fertility. In the airways, hundreds of motile cilia present on the surface of a multiciliated epithelia cell beat coordinately to protect the epithelium from bacteria, viruses, and harmful particulates. During multiciliated cell differentiation, motile cilia are templated from basal bodies, each extending a basal foot-an appendage linking motile cilia together to ensure coordinated beating. Here, we demonstrate that among the many motile cilia of a multiciliated cell, a hybrid c...
Source: Developmental Cell - October 6, 2020 Category: Cytology Authors: Liu Z, Nguyen QPH, Nanjundappa R, Delgehyr N, Megherbi A, Doherty R, Thompson J, Jackson C, Albulescu A, Heng YM, Lucas JS, Dell SD, Meunier A, Czymmek K, Mahjoub MR, Mennella V Tags: Dev Cell Source Type: research

Comparative Super-Resolution Mapping of Basal Feet Reveals a Modular but Distinct Architecture in Primary and Motile Cilia.
Abstract In situ molecular architecture analysis of organelles and protein assemblies is essential to understanding the role of individual components and their cellular function, and to engineering new molecular functionalities. Through a super-resolution-driven approach, here we characterize the organization of the ciliary basal foot, an appendage of basal bodies whose main role is to provide a point of anchoring to the microtubule cytoskeleton. Quantitative image analysis shows that the basal foot is organized into three main regions linked by elongated coiled-coil proteins, revealing a conserved modular archite...
Source: Developmental Cell - October 6, 2020 Category: Cytology Authors: Nguyen QPH, Liu Z, Albulescu A, Ouyang H, Zlock L, Coyaud E, Laurent E, Finkbeiner W, Moraes TJ, Raught B, Mennella V Tags: Dev Cell Source Type: research

Inflammation of the Embryonic Choroid Plexus Barrier following Maternal Immune Activation.
Abstract The choroid plexus (ChP) regulates brain development by secreting instructive cues and providing a protective brain barrier. Here, we show that polyI:C-mediated maternal immune activation leads to an inflammatory response in the developing embryonic mouse brain that manifests as pro-inflammatory cerebrospinal fluid (CSF) and accumulation of ChP macrophages. Elevation of CSF-CCL2 was sufficient to drive ChP immune cell recruitment, activation, and proliferation. In addition, ChP macrophages abandoned their regular tiling pattern and relocated to the ChP-free margin where they breached the weakened epitheli...
Source: Developmental Cell - October 5, 2020 Category: Cytology Authors: Cui J, Shipley FB, Shannon ML, Alturkistani O, Dani N, Webb MD, Sugden AU, Andermann ML, Lehtinen MK Tags: Dev Cell Source Type: research

A New Link to Primate Heart Development.
Abstract Long non-coding RNAs (lncRNAs) are important regulators of development. In this issue of Developmental Cell, Wilson et al. utilize pluripotent stem cell models to demonstrate that a primate lncRNA, BANCR, is primarily expressed in fetal cardiomyocytes and promotes cell migration. PMID: 32991832 [PubMed - as supplied by publisher] (Source: Developmental Cell)
Source: Developmental Cell - September 27, 2020 Category: Cytology Authors: Nelakanti RV, Xiao AZ Tags: Dev Cell Source Type: research

Transcriptional Decoding of Morphogen Gradients during Development.
Abstract The ability to visualize transcription in real time in living organisms has enabled a new generation of gene expression studies in development. In this issue of Developmental Cell, Hoppe et al. show that the bone morphogenetic protein gradient is decoded through frequency modulation encoded by enhancers. PMID: 32991833 [PubMed - as supplied by publisher] (Source: Developmental Cell)
Source: Developmental Cell - September 27, 2020 Category: Cytology Authors: Garcia GR, Larson DR Tags: Dev Cell Source Type: research

ATACing Somatic Embryogenesis.
Abstract How does auxin induce somatic embryogenesis? In this issue of Developmental Cell, Wang et al. uncover a regulatory role for auxin in the dynamics of chromatin accessibility and gene expression, which is critical for the establishment of developmental time-specific transcriptional regulatory networks orchestrating somatic-to-embryonic cell reprogramming and somatic embryo development. PMID: 32991834 [PubMed - as supplied by publisher] (Source: Developmental Cell)
Source: Developmental Cell - September 27, 2020 Category: Cytology Authors: Xu J Tags: Dev Cell Source Type: research

Translating Messages in Different Neighborhoods.
yer E Abstract Cellular distribution of biomolecules is important for regulating their function. In this issue of Developmental Cell, Chouaib et al., 2020 employ genetically tagged human cell lines to investigate the subcellular distribution of specific mRNAs and their encoded proteins, revealing several instances of localized translation with distinctive regulatory implications. PMID: 32991835 [PubMed - as supplied by publisher] (Source: Developmental Cell)
Source: Developmental Cell - September 27, 2020 Category: Cytology Authors: Chin A, Lécuyer E Tags: Dev Cell Source Type: research

In  Vitro and In Vivo Development of the Human Airway at Single-Cell Resolution.
In Vitro and In Vivo Development of the Human Airway at Single-Cell Resolution. Dev Cell. 2020 Sep 28;54(6):818 Authors: Miller AJ, Yu Q, Czerwinski M, Tsai YH, Conway RF, Wu A, Holloway EM, Walker T, Glass IA, Treutlein B, Camp JG, Spence JR PMID: 32991836 [PubMed - as supplied by publisher] (Source: Developmental Cell)
Source: Developmental Cell - September 27, 2020 Category: Cytology Authors: Miller AJ, Yu Q, Czerwinski M, Tsai YH, Conway RF, Wu A, Holloway EM, Walker T, Glass IA, Treutlein B, Camp JG, Spence JR Tags: Dev Cell Source Type: research

A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development.
Abstract The etiology of congenital heart defects (CHDs), which are among the most common human birth defects, is poorly understood because of its complex genetic architecture. Here, we show that two genes implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a receptor-like ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased ...
Source: Developmental Cell - September 18, 2020 Category: Cytology Authors: Kong JH, Young CB, Pusapati GV, Patel CB, Ho S, Krishnan A, Lin JI, Devine W, Moreau de Bellaing A, Athni TS, Aravind L, Gunn TM, Lo CW, Rohatgi R Tags: Dev Cell Source Type: research

Recording EMT Activity by Lineage Tracing during Metastasis.
ain C Abstract In this issue of Developmental Cell, Li et al. develop a novel lineage tracing system to record EMT activity during lung metastasis of mammary tumors. Using EMT-tracer mouse models, they reveal that N-cadherin is transiently expressed by most metastasis-initiating cells and demonstrate its functional importance during the metastatic cascade. PMID: 32931747 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - September 13, 2020 Category: Cytology Authors: Vieugué P, Blanpain C Tags: Dev Cell Source Type: research

Buckling Up from the Bottom.
Abstract In this issue of Developmental Cell, Trushko et al. (2020) develop a bottom-up approach to understand the physics underlying confined epithelial monolayer folding. Investigating this process is currently unattainable in vivo but is essential to our understanding of tissue formation from the gastrulating blastula to the developing nervous system. PMID: 32931748 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - September 13, 2020 Category: Cytology Authors: Matejčić M, Trepat X Tags: Dev Cell Source Type: research

Dally-like Is Unlike Dally in Assisting Wingless Spread.
Abstract Lipidated morphogens can spread within tissues to regulate cell fate during development or tissue repair. How these insoluble molecules reach distant target cells remains unclear. Reporting in Nature, McGough et al. (2020) reveal the secret of how the cell-surface proteoglycan Dally-like-protein (Dlp) promotes long-range signaling of the palmitoylated morphogen Wingless. PMID: 32931749 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - September 13, 2020 Category: Cytology Authors: Grobe K, Guerrero I Tags: Dev Cell Source Type: research

The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis.
Abstract Extracellular pH is usually maintained around 7.4 in multicellular organisms, and cells are optimized to proliferate under this condition. Here, we find cells can adapt to a more acidic pH of 6.5 and become addicted to this acidic microenvironment by expressing phosphatase of regenerating liver (PRL), a driver of cancer malignancy. Genome-scale CRISPR-Cas9 knockout screening and subsequent analyses revealed that PRL promotes H+ extrusion and acid addiction by stimulating lysosomal exocytosis. Further experiments using cultured cells and Caenorhabditis elegans clarified the molecular link between PRL and l...
Source: Developmental Cell - September 7, 2020 Category: Cytology Authors: Funato Y, Yoshida A, Hirata Y, Hashizume O, Yamazaki D, Miki H Tags: Dev Cell Source Type: research

Mechanical Coupling Coordinates the Co-elongation of Axial and Paraxial Tissues in Avian Embryos.
Pourquié O Abstract Tissues undergoing morphogenesis impose mechanical effects on one another. How developmental programs adapt to or take advantage of these effects remains poorly explored. Here, using a combination of live imaging, modeling, and microsurgical perturbations, we show that the axial and paraxial tissues in the forming avian embryonic body coordinate their rates of elongation through mechanical interactions. First, a cell motility gradient drives paraxial presomitic mesoderm (PSM) expansion, resulting in compression of the axial neural tube and notochord; second, elongation of axial tissues d...
Source: Developmental Cell - September 4, 2020 Category: Cytology Authors: Xiong F, Ma W, Bénazéraf B, Mahadevan L, Pourquié O Tags: Dev Cell Source Type: research

The Rag GTPase Regulates the Dynamic Behavior of TSC Downstream of Both Amino Acid and Growth Factor Restriction.
Abstract The dysregulation of the metabolic regulator TOR complex I (TORC1) contributes to a wide array of human pathologies. Tuberous sclerosis complex (TSC) is a potent inhibitor of TORC1. Here, we demonstrate that the Rag GTPase acts in both the amino-acid-sensing and growth factor signaling pathways to control TORC1 activity through the regulation of TSC dynamics in HeLa cells and Drosophila. We find that TSC lysosomal-cytosolic exchange increases in response to both amino acid and growth factor restriction. Moreover, the rate of exchange mirrors TSC function, with depletions of the Rag GTPase blocking TSC lys...
Source: Developmental Cell - September 2, 2020 Category: Cytology Authors: Yang S, Zhang Y, Ting CY, Bettedi L, Kim K, Ghaniam E, Lilly MA Tags: Dev Cell Source Type: research

An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells.
Abstract The Ras/PI3K/extracellular signal-regulated kinases (ERK) signaling network plays fundamental roles in cell growth, survival, and migration and is frequently activated in cancer. Here, we show that the activities of the signaling network propagate as coordinated waves, biased by growth factor, which drives actin-based protrusions in human epithelial cells. The network exhibits hallmarks of biochemical excitability: the annihilation of oppositely directed waves, all-or-none responsiveness, and refractoriness. Abrupt perturbations to Ras, PI(4,5)P2, PI(3,4)P2, ERK, and TORC2 alter the threshold, observation...
Source: Developmental Cell - August 30, 2020 Category: Cytology Authors: Zhan H, Bhattacharya S, Cai H, Iglesias PA, Huang CH, Devreotes PN Tags: Dev Cell Source Type: research

Distinct Cation Gradients Power Cholesterol Transport at Different Key Points in the Hedgehog Signaling Pathway.
Abstract Cholesterol plays two critical roles in Hedgehog signaling, a fundamental pathway in animal development and cancer: it covalently modifies the Sonic hedgehog (SHH) ligand, restricting its release from producing cells, and directly activates Smoothened in responding cells. In both contexts, a membrane protein related to bacterial RND transporters regulates cholesterol: Dispatched1 controls release of cholesterylated SHH, and Patched1 antagonizes Smoothened activation by cholesterol. The mechanism and driving force for eukaryotic RND proteins, including Dispatched1 and Patched1, are unknown. Here, we show t...
Source: Developmental Cell - August 24, 2020 Category: Cytology Authors: Petrov K, Wierbowski BM, Liu J, Salic A Tags: Dev Cell Source Type: research

An Architect of the Hindbrain: DDX3X Regulates Normal and Malignant Development.
Abstract Hallmark mutations in WNT and SHH medulloblastoma are usually distinct, but DDX3X is often mutated in both subgroups. In this issue of Developmental Cell, Patmore et al. identify Ddx3x as essential for hindbrain patterning, cell fate determination, and as a tumor suppressor gene that restricts cell lineage progression in tumorigenesis. PMID: 32841591 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - August 23, 2020 Category: Cytology Authors: Hwang GH, Segal RA Tags: Dev Cell Source Type: research

Why Airway Gland Secretions Are Abnormally Sticky in Cystic Fibrosis, and Why Not Much Can Be Done About It.
Abstract In this issue of Developmental Cell, Xie et al. show that in cystic fibrosis, airway gland mucus gels form under conditions of high acidity and protein concentration. This causes them to be unusually stiff. This abnormal rheology cannot be corrected by changing pH or calcium levels in the bathing medium. PMID: 32841592 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - August 23, 2020 Category: Cytology Authors: Widdicombe JH Tags: Dev Cell Source Type: research

Building Relationships: A Role for Innexins in Tissue Formation.
Abstract The mechanisms that govern cell interactions during organ formation are not fully understood. In this issue of Developmental Cell, Miao et al. demonstrate a channel-independent role for gap junction proteins in the establishment of contacts between three cell types that build up the micropyle during oocyte development in Drosophila. PMID: 32841593 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - August 23, 2020 Category: Cytology Authors: Labbaf Z, Raz E Tags: Dev Cell Source Type: research

Intestinal Regeneration: Regulation by the Microenvironment.
Abstract Damage to the intestinal stem cell niche can result from mechanical stress, infections, chronic inflammation or cytotoxic therapies. Progenitor cells can compensate for insults to the stem cell population through dedifferentiation. The microenvironment modulates this regenerative response by influencing the activity of signaling pathways, including Wnt, Notch, and YAP/TAZ. For instance, mesenchymal cells and immune cells become more abundant after damage and secrete signaling molecules that promote the regenerative process. Furthermore, regeneration is influenced by the nutritional state, microbiome, and ...
Source: Developmental Cell - August 23, 2020 Category: Cytology Authors: Hageman JH, Heinz MC, Kretzschmar K, van der Vaart J, Clevers H, Snippert HJG Tags: Dev Cell Source Type: research

Differentiation of Human Intestinal Organoids with Endogenous Vascular Endothelial Cells.
Abstract Human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) lack some cellular populations found in the native organ, including vasculature. Using single-cell RNA sequencing (scRNA-seq), we have identified a population of endothelial cells (ECs) present early in HIO differentiation that declines over time in culture. Here, we developed a method to expand and maintain this endogenous population of ECs within HIOs (vHIOs). Given that ECs possess organ-specific gene expression, morphology, and function, we used bulk RNA-seq and scRNA-seq to interrogate the developing human intestine, lung, and kid...
Source: Developmental Cell - August 23, 2020 Category: Cytology Authors: Holloway EM, Wu JH, Czerwinski M, Sweet CW, Wu A, Tsai YH, Huang S, Stoddard AE, Capeling MM, Glass I, Spence JR Tags: Dev Cell Source Type: research

Microtubules Enhance Mesoscale Effective Diffusivity in the Crowded Metaphase Cytoplasm.
Abstract Mesoscale macromolecular complexes and organelles, tens to hundreds of nanometers in size, crowd the eukaryotic cytoplasm. It is therefore unclear how mesoscale particles remain sufficiently mobile to regulate dynamic processes such as cell division. Here, we study mobility across dividing cells that contain densely packed, dynamic microtubules, comprising the metaphase spindle. In dividing human cells, we tracked 40 nm genetically encoded multimeric nanoparticles (GEMs), whose sizes are commensurate with the inter-filament spacing in metaphase spindles. Unexpectedly, the effective diffusivity of GEM...
Source: Developmental Cell - August 17, 2020 Category: Cytology Authors: Carlini L, Brittingham GP, Holt LJ, Kapoor TM Tags: Dev Cell Source Type: research

Mitotic ER Exit Site Disassembly and Reassembly Are Regulated by the Phosphorylation Status of TANGO1.
In this study, we identified TANGO1 as a regulator of ER exit site disassembly during mitosis. TANGO1 phosphorylation was observed to be coordinately regulated by a kinase (CK1) and a phosphatase (PP1). CK1-mediated TANGO1 phosphorylation reduces binding to Sec16, leading to the disassembly of ER exit sites. CK1 constantly phosphorylates TANGO1, whereas PP1-mediated dephosphorylation of TANGO1 decreases during mitosis. Thus, the phosphorylation status of TANGO1, which is controlled by balanced activities of the kinase CK1 and the phosphatase PP1, regulates the organization of ER exit sites during the cell cycle. PMID:...
Source: Developmental Cell - August 11, 2020 Category: Cytology Authors: Maeda M, Komatsu Y, Saito K Tags: Dev Cell Source Type: research

Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production.
Abstract Embryonic hematopoietic stem and progenitor cells (HSPCs) robustly proliferate while maintaining multilineage potential in vivo; however, an incomplete understanding of spatiotemporal cues governing their generation has impeded robust production from human induced pluripotent stem cells (iPSCs) in vitro. Using the zebrafish model, we demonstrate that NLRP3 inflammasome-mediated interleukin-1-beta (IL1β) signaling drives HSPC production in response to metabolic activity. Genetic induction of active IL1β or pharmacologic inflammasome stimulation increased HSPC number as assessed by in si...
Source: Developmental Cell - August 9, 2020 Category: Cytology Authors: Frame JM, Kubaczka C, Long TL, Esain V, Soto RA, Hachimi M, Jing R, Shwartz A, Goessling W, Daley GQ, North TE Tags: Dev Cell Source Type: research

Persistent DNA Damage and Senescence in the Placenta Impacts Developmental Outcomes of Embryos.
Abstract Cohesin is an evolutionarily conserved chromosome-associated protein complex essential for chromosome segregation, gene expression, and repair of DNA damage. Mutations that affect this complex cause the human developmental disorder Cornelia de Lange syndrome (CdLS), thought to arise from defective embryonic transcription. We establish a significant role for placental defects in the development of CdLS mouse embryos (Nipbl and Hdac8). Placenta is a naturally senescent tissue; we demonstrate that persistent DNA damage potentiates senescence and activates cytokine signaling. Mutant embryo developmental outco...
Source: Developmental Cell - August 9, 2020 Category: Cytology Authors: Singh VP, McKinney S, Gerton JL Tags: Dev Cell Source Type: research

Linking Matrix Rigidity with EMT and Cancer Invasion.
Abstract The extracellular matrix (ECM) plays a major role in cancer progression through its increased deposition and alignment. In this issue of Developmental Cell, Fattet et al. reveal a pathway in which ECM stiffness promotes EPHA2/LYN complex activation, leading to TWIST1 nuclear localization and triggering EMT in breast cancer. PMID: 32781020 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - August 9, 2020 Category: Cytology Authors: Ros M, Sala M, Saltel F Tags: Dev Cell Source Type: research

Keep Calm and the Placenta Will Carry On.
Abstract A fully functional placenta is critical for a successful pregnancy. In this issue of Developmental Cell, Singh et al. reveal that excessive placental DNA damage in murine models for Cornelia de Lange syndrome results in an inefficient and senescent placenta that impairs embryonic development. PMID: 32781021 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - August 9, 2020 Category: Cytology Authors: Perez-Garcia V, Turco MY Tags: Dev Cell Source Type: research

Nuclear sizER in Early Development.
Abstract In this issue of Developmental Cell, Mukherjee et al. (2020) investigate control of nuclear growth by live imaging of early embryogenesis, perturbations of blastomere dimensions, and reconstitution in vitro. The authors uncover new mechanisms of nuclear size scaling by the amount of inherited perinuclear ER and duration of interphase. PMID: 32781022 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - August 9, 2020 Category: Cytology Authors: Chen H, Good MC Tags: Dev Cell Source Type: research

A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle.
Abstract Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term "paligenosis" to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifr...
Source: Developmental Cell - August 5, 2020 Category: Cytology Authors: Miao ZF, Lewis MA, Cho CJ, Adkins-Threats M, Park D, Brown JW, Sun JX, Burclaff JR, Kennedy S, Lu J, Mahar M, Vietor I, Huber LA, Davidson NO, Cavalli V, Rubin DC, Wang ZN, Mills JC Tags: Dev Cell Source Type: research

Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment.
Abstract The crosstalk between tumor cells and the adjacent normal epithelium contributes to cancer progression, but its regulators have remained elusive. Here, we show that breast cancer cells maintained in hypoxia release small extracellular vesicles (sEVs) that activate mitochondrial dynamics, stimulate mitochondrial movements, and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in AKT serine/threonine kinase (Akt) activation, membrane focal adhesion turnover, and increased epithelial cell migration. RNA sequencing profiling identified integrin-linked...
Source: Developmental Cell - August 3, 2020 Category: Cytology Authors: Bertolini I, Ghosh JC, Kossenkov AV, Mulugu S, Krishn SR, Vaira V, Qin J, Plow EF, Languino LR, Altieri DC Tags: Dev Cell Source Type: research

Modulation of the Promoter Activation Rate Dictates the Transcriptional Response to Graded BMP Signaling Levels in the Drosophila Embryo.
Abstract Morphogen gradients specify cell fates during development, with a classic example being the bone morphogenetic protein (BMP) gradient's conserved role in embryonic dorsal-ventral axis patterning. Here, we elucidate how the BMP gradient is interpreted in the Drosophila embryo by combining live imaging with computational modeling to infer transcriptional burst parameters at single-cell resolution. By comparing burst kinetics in cells receiving different levels of BMP signaling, we show that BMP signaling controls burst frequency by regulating the promoter activation rate. We provide evidence that the promot...
Source: Developmental Cell - August 2, 2020 Category: Cytology Authors: Hoppe C, Bowles JR, Minchington TG, Sutcliffe C, Upadhyai P, Rattray M, Ashe HL Tags: Dev Cell Source Type: research

CRISPR-Cas13d Induces Efficient mRNA Knockdown in Animal Embryos.
rado A, Málaga-Trillo E, Takacs CM, Bazzini AA, Moreno-Mateos MA Abstract Early embryonic development is driven exclusively by maternal gene products deposited into the oocyte. Although critical in establishing early developmental programs, maternal gene functions have remained elusive due to a paucity of techniques for their systematic disruption and assessment. CRISPR-Cas13 systems have recently been employed to degrade RNA in yeast, plants, and mammalian cell lines. However, no systematic study of the potential of Cas13 has been carried out in an animal system. Here, we show that CRISPR-RfxCas13d (CasRx)...
Source: Developmental Cell - July 31, 2020 Category: Cytology Authors: Kushawah G, Hernandez-Huertas L, Abugattas-Nuñez Del Prado J, Martinez-Morales JR, DeVore ML, Hassan H, Moreno-Sanchez I, Tomas-Gallardo L, Diaz-Moscoso A, Monges DE, Guelfo JR, Theune WC, Brannan EO, Wang W, Corbin TJ, Moran AM, Sánchez Alvarado A, Má Tags: Dev Cell Source Type: research

Chromatin Accessibility Dynamics and a Hierarchical Transcriptional Regulatory Network Structure for Plant Somatic Embryogenesis.
Abstract Plant somatic embryogenesis refers to a phenomenon where embryos develop from somatic cells in the absence of fertilization. Previous studies have revealed that the phytohormone auxin plays a crucial role in somatic embryogenesis by inducing a cell totipotent state, although its underlying mechanism is poorly understood. Here, we show that auxin rapidly rewires the cell totipotency network by altering chromatin accessibility. The analysis of chromatin accessibility dynamics further reveals a hierarchical gene regulatory network underlying somatic embryogenesis. Particularly, we find that the embryonic nat...
Source: Developmental Cell - July 27, 2020 Category: Cytology Authors: Wang FX, Shang GD, Wu LY, Xu ZG, Zhao XY, Wang JW Tags: Dev Cell Source Type: research

Endogenous Retrovirus-Derived lncRNA BANCR Promotes Cardiomyocyte Migration in Humans and Non-human Primates.
Abstract Transposable elements (TEs) comprise nearly half of the human genome and are often transcribed or exhibit cis-regulatory properties with unknown function in specific processes such as heart development. In the case of endogenous retroviruses (ERVs), a TE subclass, experimental interrogation is constrained as many are primate-specific or human-specific. Here, we use primate pluripotent stem-cell-derived cardiomyocytes that mimic fetal cardiomyocytes in vitro to discover hundreds of ERV transcripts from the primate-specific MER41 family, some of which are regulated by the cardiogenic transcription fact...
Source: Developmental Cell - July 27, 2020 Category: Cytology Authors: Wilson KD, Ameen M, Guo H, Abilez OJ, Tian L, Mumbach MR, Diecke S, Qin X, Liu Y, Yang H, Ma N, Gaddam S, Cunningham NJ, Gu M, Neofytou E, Prado M, Hildebrandt TB, Karakikes I, Chang HY, Wu JC Tags: Dev Cell Source Type: research

Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting.
Abstract Lipid droplet (LD) formation from the endoplasmic reticulum (ER) is accompanied by the targeting and accumulation of specific hydrophobic, membrane-embedded proteins on LDs. The determinants of this process are unknown. Here, we study the hydrophobic membrane motifs of two Drosophila melanogaster proteins, GPAT4 and ALG14, that utilize this pathway, and we identify crucial sequence features that mediate LD accumulation. Molecular dynamics simulations and studies in cells reveal that LD targeting of these motifs requires deeply inserted tryptophans that have lower free energy in the LD oil phase and positi...
Source: Developmental Cell - July 26, 2020 Category: Cytology Authors: Olarte MJ, Kim S, Sharp ME, Swanson JMJ, Farese RV, Walther TC Tags: Dev Cell Source Type: research

Acidic Submucosal Gland pH and Elevated Protein Concentration Produce Abnormal Cystic Fibrosis Mucus.
Abstract In response to respiratory insults, airway submucosal glands secrete copious mucus strands to increase mucociliary clearance and protect the lung. However, in cystic fibrosis, stimulating submucosal glands has the opposite effect, disrupting mucociliary transport. In cystic fibrosis (CF) pigs, loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channels produced submucosal gland mucus that was abnormally acidic with an increased protein concentration. To test whether these variables alter mucus, we produced a microfluidic model of submucosal glands using mucus vesicles from banana slu...
Source: Developmental Cell - July 22, 2020 Category: Cytology Authors: Xie Y, Lu L, Tang XX, Moninger TO, Huang TJ, Stoltz DA, Welsh MJ Tags: Dev Cell Source Type: research

Ankmy2 Prevents Smoothened-Independent Hyperactivation of the Hedgehog Pathway via Cilia-Regulated Adenylyl Cyclase Signaling.
Abstract The mechanisms underlying subcellular targeting of cAMP-generating adenylyl cyclases and processes regulated by their compartmentalization are poorly understood. Here, we identify Ankmy2 as a repressor of the Hedgehog pathway via adenylyl cyclase targeting. Ankmy2 binds to multiple adenylyl cyclases, determining their maturation and trafficking to primary cilia. Mice lacking Ankmy2 are mid-embryonic lethal. Knockout embryos have increased Hedgehog signaling and completely open neural tubes showing co-expansion of all ventral neuroprogenitor markers, comparable to the loss of the Hedgehog receptor Patched1...
Source: Developmental Cell - July 20, 2020 Category: Cytology Authors: Somatilaka BN, Hwang SH, Palicharla VR, White KA, Badgandi H, Shelton JM, Mukhopadhyay S Tags: Dev Cell Source Type: research

Communication at a Distance.
PMID: 32693051 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - July 19, 2020 Category: Cytology Authors: Developmental Cell Editorial Team Tags: Dev Cell Source Type: research

Into Thin Air: Hypoxia Drives Metabolic and Epigenomic Deregulation of Lethal Pediatric Ependymoma.
Abstract Posterior fossa type A (PFA) ependymoma is a lethal pediatric brain tumor proposed to be driven solely by epigenetic deregulation. Michealraj et al. (2020) demonstrate that hypoxia reprograms PFA metabolism and, subsequently, the epigenome toward H3K27 hypomethylation, mirroring transcriptional and metabolic signatures of gliogenic progenitors involved in embryonal hindbrain development. PMID: 32693052 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - July 19, 2020 Category: Cytology Authors: Englinger B, Hack OA, Filbin MG Tags: Dev Cell Source Type: research

Endothelial Cells Don't Waste: Endothelial-Derived Lactate Boosts Muscle Regeneration.
Abstract Blood vessels are an essential interface between the circulation and tissue that deploy signaling molecules (angiocrines) for organ development, homeostasis, and repair. In a recent issue of Cell Metabolism, Zhang et al. (2020) identify lactate as an endothelial-derived signal promoting ischemic muscle regeneration, establishing metabolites as a new angiocrine class. PMID: 32693053 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - July 19, 2020 Category: Cytology Authors: Castro M, Andrade J, Potente M Tags: Dev Cell Source Type: research

Nutrients men-TOR β-Cells to Adulthood.
Nutrients men-TOR β-Cells to Adulthood. Dev Cell. 2020 Jul 20;54(2):140-141 Authors: Katsumoto K, Grapin-Botton A Abstract A major trigger of adult β-cell insulin secretion is glucose. In a recent issue of Cell Metabolism, Helman and colleagues show that in fetuses insulin secretion depends on the activation of mTOR by amino acids and that reducing amino acids promotes maturation of β-cells derived from pluripotent stem cells. PMID: 32693054 [PubMed - in process] (Source: Developmental Cell)
Source: Developmental Cell - July 19, 2020 Category: Cytology Authors: Katsumoto K, Grapin-Botton A Tags: Dev Cell Source Type: research