Keratins Are Going Nuclear
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Development and Maintenance of Epidermal Stem Cells in Skin Adnexa
International Journal of Molecular Sciences Review Development and Maintenance of Epidermal Stem Cells in Skin Adnexa Jaroslav Mokry * and Rishikaysh Pisal Medical Faculty, Charles University, 500 03 Hradec Kralove, Czech Republic; [email protected] * Correspondence: [email protected] Received: 30 October 2020; Accepted: 18 December 2020; Published: 20 December 2020 Abstract: The skin surface is modified by numerous appendages. These structures arise from epithelial stem cells (SCs) through the induction of epidermal placodes as a result of local signalling interplay with mesenchymal cells based on the Wnt–(Dkk4)–Eda–Shh cascade. Slight modifications of the cascade, with the participation of antagonistic signalling, decide whether multipotent epidermal SCs develop in interfollicular epidermis, scales, hair/feather follicles, nails or skin glands. This review describes the roles of epidermal SCs in the development of skin adnexa and interfollicular epidermis, as well as their maintenance. Each skin structure arises from distinct pools of epidermal SCs that are harboured in specific but different niches that control SC behaviour. Such relationships explain differences in marker and gene expression patterns between particular SC subsets. The activity of well-compartmentalized epidermal SCs is orchestrated with that of other skin cells not only along the hair cycle but also in the course of skin regeneration following injury. This review highlights several membrane markers, cytoplasmic proteins and transcription factors associated with epidermal SCs. Keywords: stem cell; epidermal placode; skin adnexa; signalling; hair pigmentation; markers; keratins 1. Epidermal Stem Cells as Units of Development 1.1. Development of the Epidermis and Placode Formation The embryonic skin at very early stages of development is covered by a surface ectoderm that is a precursor to the epidermis and its multiple derivatives. -
Haploinsufficiency of the Schizophrenia and Autism Risk Gene
Haan et al. Translational Psychiatry (2021) 11:313 https://doi.org/10.1038/s41398-021-01415-6 Translational Psychiatry ARTICLE Open Access Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms Niels Haan 1,LauraJ.Westacott1, Jenny Carter1,MichaelJ.Owen 1, William P. Gray1,2,3, Jeremy Hall 1,3 and Lawrence S. Wilkinson1,3,4 Abstract Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; with strong evidence for involvement in psychopathology. Introduction (BP1–BP2) psychiatric phenotype due to evidence of Many psychiatric conditions show high heritability. CYFIP1’s involvement in a range of synaptic functions, Recent genetic studies in schizophrenia for example have including key roles in dendritic spine morphology and – identified up to 160 loci that increase risk for the dis- branching9 11. -
Differential Expression of Two Neuronal Intermediate-Filament Proteins, Peripherin and the Low-Molecular-Mass Neurofilament Prot
The Journal of Neuroscience, March 1990, fO(3): 764-764 Differential Expression of Two Neuronal Intermediate-Filament Proteins, Peripherin and the Low-Molecular-Mass Neurofilament Protein (NF-L), During the Development of the Rat Michel Escurat,’ Karima Djabali,’ Madeleine Gumpel,2 Franqois Gras,’ and Marie-Madeleine Portier’ lCollBne de France, Biochimie Cellulaire, 75231 Paris Cedex 05, France, *HBpital de la Salpktricke, Unite INSERM 134, 75651Paris Cedex 13, France The expression of peripherin, an intermediate filament pro- and Freeman, 1978), now more generally referred to respectively tein, had been shown by biochemical methods to be local- as high-, middle-, and low-molecular-mass NFP (NF-H, NF-M, ized in the neurons of the PNS. Using immunohistochemical and NF-L). These proteins are expressed in most mature neu- methods, we analyzed this expression more extensively dur- ronal populations belonging either to the CNS or to the PNS; ing the development of the rat and compared it with that of developing neurons generally do not express any of them until the low-molecular-mass neurofilament protein (NF-L), which they become postmitotic (Tapscott et al., 198 la). is expressed in every neuron of the CNS and PNS. We, however, described another IFP with a molecular weight The immunoreactivity of NF-L is first apparent at the 25 of about 57 kDa, which we had first observed in mouse neu- somite stage (about 11 d) in the ventral horn of the spinal roblastoma cell lines and which was also expressed in rat pheo- medulla and in the posterior part of the rhombencephalon. chromocytoma PC1 2 cell line. -
Transgenic Cyclooxygenase-2 Overexpression Sensitizes Mouse Skin for Carcinogenesis
Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis Karin Mu¨ ller-Decker*†, Gitta Neufang*, Irina Berger‡, Melanie Neumann*, Friedrich Marks*, and Gerhard Fu¨ rstenberger* *Research Program Tumor Cell Regulation, Deutsches Krebsforschungszentrum, and ‡Department of Pathology, Ruprecht-Karls-University, 69120 Heidelberg, Germany Edited by Philip Needleman, Pharmacia Corporation, St. Louis, MO, and approved July 29, 2002 (received for review May 30, 2002) Genetic and pharmacological evidence suggests that overexpres- there is a causal relationship between COX-2 overexpression sion of cyclooxygenase-2 (COX-2) is critical for epithelial carcino- and tumor development. Recently, we have shown that the genesis and provides a major target for cancer chemoprevention keratin 5 (K5) promoter-driven overexpression of COX-2 in by nonsteroidal antiinflammatory drugs. Transgenic mouse lines basal cells of interfollicular epidermis and the pilosebaceous unit with keratin 5 promoter-driven COX-2 overexpression in basal led to a preneoplastic skin phenotype in 4 of 4 high-expression epidermal cells exhibit a preneoplastic skin phenotype. As shown mouse lines (15). here, this phenotype depends on the level of COX-2 expression and To delineate COX-2 functions for carcinogenesis, we have COX-2-mediated prostaglandin accumulation. The transgenics did used the initiation–promotion model (2) for the induction of skin not develop skin tumors spontaneously but did so after a single tumors in wild-type (wt) NMRI mice and COX-2 transgenic application of an initiating dose of the carcinogen 7,12-dimethyl- mouse lines. This multistage model allows the analysis of the benz[a]anthracene (DMBA). Long-term treatment with the tumor carcinogenic process in terms of distinct stages, i.e., initiation by promoter phorbol 12-myristate 13-acetate, as required for tumor- application of a subcarcinogenic dose of a carcinogen such as igenesis in wild-type mice, was not necessary for transgenics. -
Absence of NEFL in Patient-Specific Neurons in Early-Onset Charcot-Marie-Tooth Neuropathy Markus T
ARTICLE OPEN ACCESS Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy Markus T. Sainio, MSc, Emil Ylikallio, MD, PhD, Laura M¨aenp¨a¨a, MSc, Jenni Lahtela, PhD, Pirkko Mattila, PhD, Correspondence Mari Auranen, MD, PhD, Johanna Palmio, MD, PhD, and Henna Tyynismaa, PhD Dr. Tyynismaa [email protected] Neurol Genet 2018;4:e244. doi:10.1212/NXG.0000000000000244 Abstract Objective We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) underlying early-onset Charcot- Marie-Tooth (CMT) disease. Methods Motor neurons were differentiated from induced pluripotent stem cells of a patient with early- onset CMT carrying a novel homozygous nonsense mutation in NEFL. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons. Results We show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient’s cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neuro- filaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most down- regulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA. Conclusions The strict neuronal specificity of neurofilament has hindered the mechanistic studies of re- cessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. -
BD Horizon™ V450 Mouse Anti-Nestin
BD Horizon™ Technical Data Sheet V450 Mouse anti-Nestin Product Information Material Number: 561551 Size: 50 tests Vol. per Test: 5 µl Clone: 25/NESTIN Immunogen: Rat Nestin aa. 402-604 Recombinant Protein Isotype: Mouse IgG1, κ Reactivity: QC Testing: Rat Reported: Human Storage Buffer: Aqueous buffered solution containing protein stabilizer and ≤0.09% sodium azide. Description The cytoskeleton consists primarily of core structural proteins that include microfilaments, microtubules, and intermediate filaments (IFs). IFs contain more than 50 distinct proteins that are organized into six different subtypes: Type I/II keratins expressed in epithelia, type III vimentin/desmin, type IV neurofilament proteins, type V nuclear lamins, and type VI nestin expressed primarily in embryonic cells. Nestin has a conserved core region (amino acids 7 to 314), which contains an α helical domain that is involved in coiled-coil assembly of IFs. The C-terminal region of nestin is similar to type IV IFs, since it contains highly charged amino acids, many glutamate residues, and an 11 amino acid repeat motif. Nestin is expressed in the cerebrum during embryonic development, in the cerebellum during early postnatal development, and in dermatomal cells and myoblasts during myogenesis. In vitro, nestin forms homodimers and homotetramers, but not IFs, and can co-assemble with type III vimentin and type IV internexin proteins. Thus, nestin is a core IF protein that is essential for proper cytoskeletal formation during neurogenesis and myogenesis. The antibody is conjugated to BD Horizon™ V450, which has been developed for use in multicolor flow cytometry experiments and is available exclusively from BD Biosciences. -
Nuclear Matrix
Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective Pierre Cau, Claire Navarro, Karim Harhouri, Patrice Roll, Sabine Sigaudy, Elise Kaspi, Sophie Perrin, Annachiara de Sandre-Giovannoli, Nicolas Lévy To cite this version: Pierre Cau, Claire Navarro, Karim Harhouri, Patrice Roll, Sabine Sigaudy, et al.. Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective. Seminars in Cell and Developmental Biology, Elsevier, 2014, 29, pp.125-147. 10.1016/j.semcdb.2014.03.021. hal-01646524 HAL Id: hal-01646524 https://hal-amu.archives-ouvertes.fr/hal-01646524 Submitted on 20 Dec 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Review Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective Pierre Cau a,b,c,∗, Claire Navarro a,b,1, Karim Harhouri a,b,1, Patrice Roll a,b,c,1,2, Sabine Sigaudy a,b,d,1,3, Elise Kaspi a,b,c,1,2, Sophie Perrin a,b,1, Annachiara De Sandre-Giovannoli a,b,d,1,3, Nicolas Lévy a,b,d,∗∗ a Aix-Marseille -
Hypomesus Transpacificus
Aquatic Toxicology 105 (2011) 369–377 Contents lists available at ScienceDirect Aquatic Toxicology jou rnal homepage: www.elsevier.com/locate/aquatox Sublethal responses to ammonia exposure in the endangered delta smelt; Hypomesus transpacificus (Fam. Osmeridae) ∗ 1 2 Richard E. Connon , Linda A. Deanovic, Erika B. Fritsch, Leandro S. D’Abronzo , Inge Werner Aquatic Toxicology Laboratory, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California 95616, United States a r t i c l e i n f o a b s t r a c t Article history: The delta smelt (Hypomesus transpacificus) is an endangered pelagic fish species endemic to the Received 9 May 2011 Sacramento-San Joaquin Estuary in Northern California, which acts as an indicator of ecosystem health Received in revised form 29 June 2011 in its habitat range. Interrogative tools are required to successfully monitor effects of contaminants upon Accepted 2 July 2011 the delta smelt, and to research potential causes of population decline in this species. We used microarray technology to investigate genome-wide effects in fish exposed to ammonia; one of multiple contami- Keywords: nants arising from wastewater treatment plants and agricultural runoff. A 4-day exposure of 57-day Hypomesus transpacificus + old juveniles resulted in a total ammonium (NH4 –N) median lethal concentration (LC50) of 13 mg/L, Delta smelt Microarray and a corresponding un-ionized ammonia (NH3) LC50 of 147 g/L. Using the previously designed delta + Biomarker smelt microarray we assessed altered gene transcription in juveniles exposed to 10 mg/L NH4 –N from Ammonia this 4-day exposure. -
Tubulin: Are They Linced?
cells Review Microtubular and Nuclear Functions of γ-Tubulin: Are They LINCed? Jana Chumová, Hana Kourová, Lucie Trögelová, Petr Halada and Pavla Binarová * Institute of Microbiology of the Czech Academy of Sciences, Vídeˇnská 1083, 142 20 Prague, Czech Republic; [email protected] (J.C.); [email protected] (H.K.); [email protected] (L.T.); [email protected] (P.H.) * Correspondence: [email protected]; Tel.: +420-241-062-130 Received: 8 February 2019; Accepted: 14 March 2019; Published: 19 March 2019 Abstract: γ-Tubulin is a conserved member of the tubulin superfamily with a function in microtubule nucleation. Proteins of γ-tubulin complexes serve as nucleation templates as well as a majority of other proteins contributing to centrosomal and non-centrosomal nucleation, conserved across eukaryotes. There is a growing amount of evidence of γ-tubulin functions besides microtubule nucleation in transcription, DNA damage response, chromatin remodeling, and on its interactions with tumor suppressors. However, the molecular mechanisms are not well understood. Furthermore, interactions with lamin and SUN proteins of the LINC complex suggest the role of γ-tubulin in the coupling of nuclear organization with cytoskeletons. γ-Tubulin that belongs to the clade of eukaryotic tubulins shows characteristics of both prokaryotic and eukaryotic tubulins. Both human and plant γ-tubulins preserve the ability of prokaryotic tubulins to assemble filaments and higher-order fibrillar networks. γ-Tubulin filaments, with bundling and aggregating capacity, are suggested to perform complex scaffolding and sequestration functions. In this review, we discuss a plethora of γ-tubulin molecular interactions and cellular functions, as well as recent advances in understanding the molecular mechanisms behind them. -
Lamin A/C Cardiomyopathy: Implications for Treatment
Current Cardiology Reports (2019) 21:160 https://doi.org/10.1007/s11886-019-1224-7 MYOCARDIAL DISEASE (A ABBATE AND G SINAGRA, SECTION EDITORS) Lamin A/C Cardiomyopathy: Implications for Treatment Suet Nee Chen1 & Orfeo Sbaizero1,2 & Matthew R. G. Taylor1 & Luisa Mestroni1 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The purpose of this review is to provide an update on lamin A/C (LMNA)-related cardiomyopathy and discuss the current recommendations and progress in the management of this disease. LMNA-related cardiomyopathy, an inherited autosomal dominant disease, is one of the most common causes of dilated cardiomyopathy and is characterized by steady progression toward heart failure and high risks of arrhythmias and sudden cardiac death. Recent Findings We discuss recent advances in the understanding of the molecular mechanisms of the disease including altered cell biomechanics, which may represent novel therapeutic targets to advance the current management approach, which relies on standard heart failure recommendations. Future therapeutic approaches include repurposed molecularly directed drugs, siRNA- based gene silencing, and genome editing. Summary LMNA-related cardiomyopathy is the focus of active in vitro and in vivo research, which is expected to generate novel biomarkers and identify new therapeutic targets. LMNA-related cardiomyopathy trials are currently underway. Keywords Lamin A/C gene . Laminopathy . Heart failure . Arrhythmias . Mechanotransduction . P53 . CRISPR–Cas9 therapy Introduction functions, including maintaining nuclear structural integrity, regulating gene expression, mechanosensing, and Mutations in the lamin A/C gene (LMNA)causelaminopathies, mechanotransduction through the lamina-associated proteins a heterogeneous group of inherited disorders including muscu- [6–11]. -
'Montalcino, a Zebrafish Model for Variegate Porphyria'
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2008 montalcino, A zebrafish model for variegate porphyria Dooley, Kimberly A ; Fraenkel, Paula G ; Langer, Nathaniel B ; Schmid, Bettina ; Davidson, Alan J ; Weber, Gerhard ; Chiang, Ken ; Foott, Helen ; Dwyer, Caitlin ; Wingert, Rebecca A ; Zhou, Yi ; Paw, Barry H ; Zon, Leonard I Abstract: OBJECTIVE Inherited or acquired mutations in the heme biosynthetic pathway leads to a debilitating class of diseases collectively known as porphyrias, with symptoms that can include anemia, cutaneous photosensitivity, and neurovisceral dysfunction. In a genetic screen for hematopoietic mutants, we isolated a zebrafish mutant, montalcino (mno), which displays hypochromic anemia and porphyria. The objective of this study was to identify the defective gene and characterize the phenotype of the zebrafish mutant. MATERIALS AND METHODS Genetic linkage analysis was utilized to identify the region harboring the mno mutation. Candidate gene analysis together with reverse transcriptase polymerase chain reaction was utilized to identify the genetic mutation, which was confirmed via allele- specific oligo hybridizations. Whole mount in situ hybridizations and o-dianisidine staining were usedto characterize the phenotype of the mno mutant. mRNA and morpholino microinjections were performed to phenocopy and/or rescue the mutant phenotype. RESULTS Homozygous mno mutant embryos have a defect in the protoporphyrinogen oxidase (ppox) gene, which encodes the enzyme that catalyzes the oxidation of protoporphyrinogen. Homozygous mutant embryos are deficient in hemoglobin, and by 36 hours post-fertilization are visibly anemic and porphyric. The hypochromic anemia of mno embryos was partially rescued by human ppox, providing evidence for the conservation of function between human and zebrafish ppox. -
Structural and Biochemical Changes Underlying a Keratoderma-Like Phenotype in Mice Lacking Suprabasal AP1 Transcription Factor Function
Citation: Cell Death and Disease (2015) 6, e1647; doi:10.1038/cddis.2015.21 OPEN & 2015 Macmillan Publishers Limited All rights reserved 2041-4889/15 www.nature.com/cddis Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function EA Rorke*,1, G Adhikary2, CA Young2, RH Rice3, PM Elias4, D Crumrine4, J Meyer4, M Blumenberg5 and RL Eckert2,6,7,8 Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased.