Slit/Robo Signaling Regulates Cell Fate Decisions in the Intestinal Stem Cell Lineage of Drosophila

SummaryIn order to maintain tissue homeostasis, cell fate decisions within stem cell lineages have to respond to the needs of the tissue. This coordination of lineage choices with regenerative demand remains poorly characterized. Here, we identify a signal from enteroendocrine cells (EEs) that controls lineage specification in the Drosophila intestine. We find that EEs secrete Slit, a ligand for the Robo2 receptor in intestinal stem cells (ISCs) that limits ISC commitment to the endocrine lineage, establishing negative feedback control of EE regeneration. Furthermore, we show that this lineage decision is made within ISCs and requires induction of the transcription factor Prospero in ISCs. Our work identifies a function for the conserved Slit/Robo pathway in the regulation of adult stem cells, establishing negative feedback control of ISC lineage specification as a critical strategy to preserve tissue homeostasis. Our results further amend the current understanding of cell fate commitment within the Drosophila ISC lineage

Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila

Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan

La sulfirédoxine, une nouvelle enzyme illustrant les deux facettes biologiques de l'H2O2 (toxicité et signalisation)

DE TRÈS NOMBREUX PROCESSUS BIOLOGIQUES REPOSENT LES PROPRIÉTÉS REDOX DES RÉSIDUS CYSTÉINES, CE QUI SUPPOSE UN CONTRÔLE STRICT DE LEUR ÉTAT D'OXYDATION.AU COURS DE L'ANALYSE DE LA RÉPONSE TRANSCRIPTIONNELLE À L'H2O2 CHEZ S. CEREVISIAE, NOUS AVONS MIS EN ÉVIDENCE UNE NOUVELLE ACTIVITÉ ENZYMATIQUE, CONSERVÉE CHEZ LES EUCARYOTES, APPELÉE SULFIRÉDOXINE, RESPONSABLE DE LA RÉDUCTION DE LA FORME OXYDÉE EN ACIDE SULFINIQUE DES PEROXYRÉDOXINES, UNE SOUS FAMILLE DES PEROXYDASES À THIOL. CETTE MODIFICATION DE LA CYSTÉINE CATALYTIQUE DES PEROXYRÉDOXINES ÉTAIT CONSIDÉRÉE COMME IRRÉVERSIBLE, ABOUTISSANT À LA PERTE DE LEUR ACTIVITÉ. LA RÉDUCTION DE L'ACIDE SULFINIQUE PAR LA SULFIRÉDOXINES NÉCESSITE L'HYDROLYSE D'ATP ET LA PRÉSENCE D'UNE CYSTÉINE CATALYTIQUE DANS LA SULFIRÉDOXINE. CECI SUGGÈRE UN MÉCANISME TOUT À ORIGINAL, REPOSANT SUR LA FORMATION D'UNE FORME PHOSPHORYLÉE DE L'ACIDE SULFINIQUE ET D'UN THIOLSULFINATE.CHEZ S. CEREVISIAE, LE SEUL RÔLE PHYSIOLOGIQUE DÉMONTRÉ DE LA SULFIRÉDOXINE EST LA RÉPARATION DES PEROXYRÉDOXINES AU COURS D'UN STRESS OXYDANT. CEPENDANT, NOUS AVONS MONTRÉ CHEZ S. POMBE QUE L'OXYDATION DE LA PEROXYRÉDOXINE EN ACIDE SULFINIQUE ET SA RÉDUCTION PAR LA SULFIRÉDOXINE CONSTITUE UN MÉCANISME DE RÉGULATION DE L'UNE DES VOIES DE SIGNALISATION DE LA RÉPONSE À L'H2O2. CE MÉCANISME PERMET L'OXYDATION, VIA LA PEROXYRÉDOXINE, DU FACTEUR DE TRANSCRIPTION PAP1 UNIQUEMENT EN PRÉSENCE DE FAIBLES DOSES D'H2O2. ENFIN, NOUS AVONS PU MONTRER QUE LA SULFIRÉDOXINE EST FONCTIONNELLE CHEZ LES EUCARYOTES SUPÉRIEURS, MAMMIFÈRES ET PLANTES, CE QUI RENFORCE L'HYPOTHÈSE DE LEUR IMPLICATION DANS LES VOIES DE SIGNALISATION CELLULAIRE IMPLIQUANT LA PRODUCTION D'H2O2 INTRACELLULAIRE..NUMEROUS BIOLOGICAL PROCESSES ARE BASED ON REDOX PROPERTIES OF CYSTEINE RESIDUES, WHICH SUPPOSE A TIGHT CONTROL OF THE MODIFICATIONS OF THESE RESIDUES.THE STUDY OF THE TRANSCRIPTIONAL RESPONSE TO H2O2 IN S. CEREVISIAE IDENTIFIED A NEW ENZYMATIC ACTIVITY, NAMED SULFIREDOXIN, WHICH IS RESPONSIBLE OF THE REDUCTION OF THE SULFINIC ACID FORMED IN PEROXIREDOXINS, A SUB-FAMILY OF THIOL PEROXIDASES. THIS MODIFICATION OF THE ACTIVE SITE CYSTEINE OF PEROXIREDOXIN WAS CONSIDERED AS IRREVERSIBLE, LEADING TO THE LOST OF THEIR ACTIVITY.THE REDUCTION REACTION CATALYSED BY SULFIREDOXIN REQUIRES ATP HYDROLYSIS AND A CONSERVED ACTIVE SITE CYSTEINE RESIDUE. WE PROPOSE A NOVEL MECHANISM OF REDUCTION FOR THIS REACTION, INVOLVING AN ACTIVATION STEP OF THE SULFINIC ACID BY PHOSPHORYLATION FOLLOWED BY THE FORMATION OF A THIOLSULFINATE.IN S. CEREVISIAE, WE DEMONSTRATED A ROLE OF SULFIREDOXIN IN PROTEIN REPAIR DURING OXIDATIVE STRESS. IN S. POMBE, WE SHOW THAT PEROXIREDOXIN OXIDATION IN SULFINIC ACID FORM AND ITS REDUCTION BY SULFIREDOXIN IS A REGULATORY MECHANISM OF A CELL SIGNALLING PATHWAY IMPLICATED IN H2O2 RESPONSE. THIS REGULATION ALLOWS THE OXIDATION OF PAP1 TRANSCRIPTION FACTOR ONLY IN A SPECIFIC RANGE OF H2O2 CONCENTRATION.FINALLY, WE SHOW THAT SULFIREDOXIN IS CONSERVED AND FUNCTIONAL IN HIGHER EUKARYOTES, MAMMALS AND PLANTS, SUPPORTING THE HYPOTHESIS OF A BIOLOGICAL ROLE OF SULFIREDOXIN IN H2O2-BASED CELL SIGNALLING PATHWAYS.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

A Sox Transcription Factor Is a Critical Regulator of Adult Stem Cell Proliferation in the Drosophila Intestine

SummaryAdult organs and their resident stem cells are constantly facing the challenge of adapting cell proliferation to tissue demand, particularly in response to environmental stresses. Whereas most stress-signaling pathways are conserved between progenitors and differentiated cells, stem cells have the specific ability to respond by increasing their proliferative rate, using largely unknown mechanisms. Here, we show that a member of the Sox family of transcription factors in Drosophila, Sox21a, is expressed in intestinal stem cells (ISCs) in the adult gut. Sox21a is essential for the proliferation of these cells during both normal epithelium turnover and repair. Its expression is induced in response to tissue damage, downstream of the Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways, to promote ISC proliferation. Although short-lived, Sox21a mutant flies show no developmental defects, supporting the notion that this factor is a specific regulator of adult stem cell proliferation

3D modeling of length and lever arm of sternocleidomastoid and scalenus muscles in respiratory movement

info:eu-repo/semantics/publishe

3D modeling of lever arm and moment generating capacity of sternocleidomastoid and scalenus muscles in respiratory movement

info:eu-repo/semantics/publishe

Morphometric analysis of the costal facet of the thoracic vertebrae

Various studies have examined morphometric features of the vertebrae to understand the functional aspects of the spine. Geometric analysis of vertebral zygapophyseal facets has also been related to functional and clinical aspects of the spine, but no quantitative investigation of the costotransverse joint facet is found in the literature. The costal facet geometry may partly determine the mechanical interaction between the rib cage and spine for trunk stabilization during functional tasks and during breathing. Therefore, the present study proposes a method for estimating the 3D geometric features of the costal facets of the first 10 thoracic vertebrae (Th1–Th10). Series of landmarks (95 ± 43) were placed on 258 costal facets from a sample of 14 asymptomatic individuals to determine their 3D location and orientation. The relative location of the costal facet was used to investigate symmetry and asymmetry components of the overall vertebrae shape variation among thoracic levels using 3D geometric morphometric methods. Results showed significant variation in sagittal orientation (inclination angle) between levels with a gradual cephalic orientation in the lower levels. No significant difference was observed on transverse orientation (declination angle). The shape of the costal facet was flatter at Th1 and from Th5 to Th10 and more concave from Th2 to Th4. An average difference of 7° between right and left facet orientation in both sagittal and transverse plane was demonstrated. Asymmetry of costal facet relative location was also detected and significantly influenced by the thoracic level. Nevertheless, location and orientation of the costal facets seem to be independent features of vertebrae morphology.info:eu-repo/semantics/publishe

The Arabidopsis thaliana sulfiredoxin is a plastidic cysteine-sulfinic acid reductase involved in the photooxidative stress response

International audienc

Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins

Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation