IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

SummaryThe maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells is essential for their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a rapid, premature loss of intestinal tissue integrity as flies age. This age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate an unexpected and novel role of the IRBIT-RNR pathway in gut homeostasis.

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Spalt modifies EGFR-mediated induction of chordotonal precursors in the embryonic PNS of Drosophila promoting the development of oenocytes

Development ◽

10.1242/dev.128.5.711 ◽

2001 ◽

Vol 128 (5) ◽

pp. 711-722 ◽

Cited By ~ 3

Author(s):

T.E. Rusten ◽

R. Cantera ◽

J. Urban ◽

G. Technau ◽

F.C. Kafatos ◽

...

Keyword(s):

Nervous System ◽

Cell Fate ◽

System Development ◽

Cell Types ◽

Nervous System Development ◽

Dual Function ◽

Evolutionarily Conserved ◽

A Cell ◽

And Migration

Genes of the spalt family encode nuclear zinc finger proteins. In Drosophila melanogaster, they are necessary for the establishment of head/trunk identity, correct tracheal migration and patterning of the wing imaginal disc. Spalt proteins display a predominant pattern of expression in the nervous system, not only in Drosophila but also in species of fish, mouse, frog and human, suggesting an evolutionarily conserved role for these proteins in nervous system development. Here we show that Spalt works as a cell fate switch between two EGFR-induced cell types, the oenocytes and the precursors of the pentascolopodial organ in the embryonic peripheral nervous system. We show that removal of spalt increases the number of scolopodia, as a result of extra secondary recruitment of precursor cells at the expense of the oenocytes. In addition, the absence of spalt causes defects in the normal migration of the pentascolopodial organ. The dual function of spalt in the development of this organ, recruitment of precursors and migration, is reminiscent of its role in tracheal formation and of the role of a spalt homologue, sem-4, in the Caenorhabditis elegans nervous system.

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Nckβ Adapter Controls Neuritogenesis by Maintaining the Cellular Paxillin Level

Molecular and Cellular Biology ◽

10.1128/mcb.01807-06 ◽

2007 ◽

Vol 27 (17) ◽

pp. 6001-6011 ◽

Cited By ~ 16

Author(s):

Shengxi Guan ◽

Mei Chen ◽

David Woodley ◽

Wei Li

Keyword(s):

Pc12 Cells ◽

Cortical Neurons ◽

State Level ◽

Cell Types ◽

Steady State Level ◽

Down Regulation ◽

Evolutionarily Conserved ◽

Rat Cortical Neurons ◽

Interfering Rna

ABSTRACT The SH2/SH3 adapter Nck has an evolutionarily conserved role in neurons, linking the cell surface signals to actin cytoskeleton-mediated responses. The mechanism, however, remains poorly understood. We have investigated the role of Nck/Nckα/Nck1 versus Grb4/Nckβ/Nck2 side-by-side in the process of mammalian neuritogenesis. Here we show that permanent genetic silencing of Nckβ, but not Nckα, completely blocked nerve growth factor-induced neurite outgrowth in PC12 cells and dramatically disrupted the axon and dendrite tree in primary rat cortical neurons. By screening for changes among the components reportedly present in complex with Nck, we found that the steady-state level of paxillin was significantly reduced in Nckβ knockdown, but not Nckα knockdown, neurons. Interestingly, Nckβ knockdown did not affect the paxillin level in glial cells and several other cell types of various tissue origins. Genetic silencing of paxillin blocked neuritogenesis, just like Nckβ knockdown. Reintroducing a nondegradable Nckβ into Nckβ short interfering RNA-expressing PC12 cells rescued paxillin from down-regulation and allowed the resumption of neuritogenesis. Forced expression of paxillin in Nckβ knockdown PC12 also rescued its capacity for neuritogenesis. Finally, Nckβ, but not Nckα, binds strongly to paxillin and treatment of the neurons with proteosome inhibitors prevented paxillin down-regulation in Nckβ knockdown neurons. Thus, Nckβ maintains paxillin stability during neuritogenesis.

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What have we learned from basic science studies on idiopathic pulmonary fibrosis?

European Respiratory Review ◽

10.1183/16000617.0029-2019 ◽

2019 ◽

Vol 28 (153) ◽

pp. 190029 ◽

Cited By ~ 5

Author(s):

Toyoshi Yanagihara ◽

Seidai Sato ◽

Chandak Upagupta ◽

Martin Kolb

Keyword(s):

Extracellular Matrix ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cellular Senescence ◽

Basic Science ◽

Science Studies ◽

Cell Types ◽

Age Related ◽

Tremendous Progress

Idiopathic pulmonary fibrosis is a fatal age-related lung disease characterised by progressive and irreversible scarring of the lung. Although the details are not fully understood, there has been tremendous progress in understanding the pathogenesis of idiopathic pulmonary fibrosis, which has led to the identification of many new potential therapeutic targets. In this review we discuss several of these advances with a focus on genetic susceptibility and cellular senescence primarily affecting epithelial cells, activation of profibrotic pathways, disease-enhancing fibrogenic cell types and the role of the remodelled extracellular matrix.

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Tribbles in normal and malignant haematopoiesis

Biochemical Society Transactions ◽

10.1042/bst20150117 ◽

2015 ◽

Vol 43 (5) ◽

pp. 1112-1115 ◽

Cited By ~ 13

Author(s):

Sarah J. Stein ◽

Ethan A. Mack ◽

Kelly S. Rome ◽

Warren S. Pear

Keyword(s):

E3 Ligase ◽

Cell Types ◽

Protein Family ◽

Conserved Motifs ◽

Tissue Specific ◽

Cellular Events ◽

Haematopoietic Cells ◽

Evolutionarily Conserved ◽

Multiple Cell

The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types.

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A tale of 2 tissues: the overlapping role of scleraxis in tendons and the heart

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0489 ◽

2014 ◽

Vol 92 (9) ◽

pp. 707-712 ◽

Cited By ~ 5

Author(s):

Michael P. Czubryt

Keyword(s):

Extracellular Matrix ◽

Cell Types ◽

Response Mechanism ◽

Growth And Remodeling ◽

Tissue Integrity ◽

Common Response ◽

The Face ◽

Physical Forces ◽

Inherent Nature

Tissue integrity in the face of external physical forces requires the production of a strong extracellular matrix (ECM) composed primarily of the protein collagen. Tendons and the heart both withstand large and changing physical forces, and emerging evidence suggests that the transcription factor scleraxis plays a central role in responding to these forces by directly regulating the production of ECM components and (or) by determining the fate of matrix-producing cell types. Thus, despite the highly disparate inherent nature of these tissues, a common response mechanism may exist to govern the development, growth, and remodeling of the ECM in response to external force.

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Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

10.1101/659128 ◽

2019 ◽

Author(s):

Kerui Huang ◽

Ting Miao ◽

Kai Chang ◽

Ping Kang ◽

Qiuhan Jiang ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Inflammatory Cytokine ◽

Cytokine Signaling ◽

Over Expression ◽

Autonomous Regulation ◽

Age Related ◽

Evolutionarily Conserved ◽

Age Dependent ◽

Import Receptor

AbstractAge is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

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Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

Cells ◽

10.3390/cells10030694 ◽

2021 ◽

Vol 10 (3) ◽

pp. 694

Author(s):

Georgios Konstantinidis ◽

Nektarios Tavernarakis

Keyword(s):

Caenorhabditis Elegans ◽

Degradation Process ◽

Pathogen Invasion ◽

Age Related ◽

Distinct Cell ◽

Evolutionarily Conserved ◽

Subsequent Degradation ◽

Membrane Organelle ◽

Neuronal Autophagy

Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode Caenorhabditis elegans.

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The Aging Stress Response and Its Implication for AMD Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21228840 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8840

Author(s):

Janusz Blasiak ◽

Elzbieta Pawlowska ◽

Anna Sobczuk ◽

Joanna Szczepanska ◽

Kai Kaarniranta

Keyword(s):

Stress Response ◽

Vision Loss ◽

The Elderly ◽

Cellular Level ◽

Age Related Macular Degeneration ◽

Age Related ◽

Evolutionarily Conserved ◽

Nutrient Signaling ◽

Amp Activated Protein Kinase

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

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Dynamin and endocytosis are required for the fusion of osteoclasts and myoblasts

The Journal of Cell Biology ◽

10.1083/jcb.201401137 ◽

2014 ◽

Vol 207 (1) ◽

pp. 73-89 ◽

Cited By ~ 46

Author(s):

Nah-Young Shin ◽

Hyewon Choi ◽

Lynn Neff ◽

Yumei Wu ◽

Hiroaki Saito ◽

...

Keyword(s):

Cell Fusion ◽

Knockout Mouse ◽

Cell Types ◽

Cytoskeletal Reorganization ◽

Knockout Mouse Model ◽

Osteoclast Precursors ◽

Evolutionarily Conserved ◽

Myoblast Cell ◽

Cell Cell

Cell–cell fusion is an evolutionarily conserved process that leads to the formation of multinucleated myofibers, syncytiotrophoblasts and osteoclasts, allowing their respective functions. Although cell–cell fusion requires the presence of fusogenic membrane proteins and actin-dependent cytoskeletal reorganization, the precise machinery allowing cells to fuse is still poorly understood. Using an inducible knockout mouse model to generate dynamin 1– and 2–deficient primary osteoclast precursors and myoblasts, we found that fusion of both cell types requires dynamin. Osteoclast and myoblast cell–cell fusion involves the formation of actin-rich protrusions closely associated with clathrin-mediated endocytosis in the apposed cell. Furthermore, impairing endocytosis independently of dynamin also prevented cell–cell fusion. Since dynamin is involved in both the formation of actin-rich structures and in endocytosis, our results indicate that dynamin function is central to the osteoclast precursors and myoblasts fusion process, and point to an important role of endocytosis in cell–cell fusion.

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