Reorganization of membrane contacts prior to apoptosis in the Drosophila retina: the role of the IrreC-rst protein

The final step of pattern formation in the developing retina of Drosophila is the elimination of excess cells between ommatidia and the differentiation of the remaining cells into secondary and tertiary pigment cells. Temporally and spatially highly regulated expression of the irregular chiasmC-roughest protein, an adhesion molecule of the immunoglobulin superfamily known to be involved in axonal pathfinding, is essential for correct sorting of cell-cell contacts in the pupal retina without which the ensuing wave of apoptosis does not occur. Irregular chiasmC-roughest accumulates strongly at the borders between primary pigment and interommatidial cells. Mutant and misexpression analysis show that this accumulation of the irregular chiasmC-roughest protein is necessary for aligning interommatidial cells in a single row. This reorganisation is a prerequisite for the identification of death candidates. Irregular chiasmC-roughest function in retinal development demonstrates the importance of specific cell contacts for assignment of the apoptotic fate.

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Implication of Contactins in Demyelinating Pathologies

Life ◽

10.3390/life11010051 ◽

2021 ◽

Vol 11 (1) ◽

pp. 51

Author(s):

Ilias Kalafatakis ◽

Maria Savvaki ◽

Theodora Velona ◽

Domna Karagogeos

Keyword(s):

Nervous System ◽

White Matter ◽

Cell Adhesion Molecules ◽

White Matter Lesions ◽

Myelinated Axon ◽

Immunoglobulin Superfamily ◽

Proper Function ◽

Myelinated Axons ◽

And Function

Demyelinating pathologies comprise of a variety of conditions where either central or peripheral myelin is attacked, resulting in white matter lesions and neurodegeneration. Myelinated axons are organized into molecularly distinct domains, and this segregation is crucial for their proper function. These defined domains are differentially affected at the different stages of demyelination as well as at the lesion and perilesion sites. Among the main players in myelinated axon organization are proteins of the contactin (CNTN) group of the immunoglobulin superfamily (IgSF) of cell adhesion molecules, namely Contactin-1 and Contactin-2 (CNTN1, CNTN2). The two contactins perform their functions through intermolecular interactions, which are crucial for myelinated axon integrity and functionality. In this review, we focus on the implication of these two molecules as well as their interactors in demyelinating pathologies in humans. At first, we describe the organization and function of myelinated axons in the central (CNS) and the peripheral (PNS) nervous system, further analyzing the role of CNTN1 and CNTN2 as well as their interactors in myelination. In the last section, studies showing the correlation of the two contactins with demyelinating pathologies are reviewed, highlighting the importance of these recognition molecules in shaping the function of the nervous system in multiple ways.

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Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

Cancers ◽

10.3390/cancers13092152 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2152

Author(s):

Fernando C. Baltanás ◽

Cynthia Mucientes-Valdivieso ◽

L. Francisco Lorenzo-Martín ◽

Natalia Fernández-Parejo ◽

Rósula García-Navas ◽

...

Keyword(s):

Stem Cell ◽

Layer Structure ◽

3D Culture ◽

Hair Follicles ◽

Specific Cell ◽

Epidermal Stem Cell ◽

Primary Keratinocytes ◽

Cell Homeostasis ◽

Primary Mouse

Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.

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Understanding the Redox Biology of Selenium in the Search of Targeted Cancer Therapies

Antioxidants ◽

10.3390/antiox9050420 ◽

2020 ◽

Vol 9 (5) ◽

pp. 420 ◽

Cited By ~ 3

Author(s):

Jeffrey M. Stolwijk ◽

Rohan Garje ◽

Jessica C. Sieren ◽

Garry R. Buettner ◽

Yousef Zakharia

Keyword(s):

Selenium Deficiency ◽

Vital Role ◽

High Dose ◽

Specific Cell ◽

Cancer Therapies ◽

Selenium Compounds ◽

Redox Biology ◽

Selenium Treatment ◽

Prevention Of Cancer

Selenium (Se) is an essential trace nutrient required for optimal human health. It has long been suggested that selenium has anti-cancer properties. However, clinical trials have shown inconclusive results on the potential of Se to prevent cancer. The suggested role of Se in the prevention of cancer is centered around its role as an antioxidant. Recently, the potential of selenium as a drug rather than a supplement has been uncovered. Selenium compounds can generate reactive oxygen species that could enhance the treatment of cancer. Transformed cells have high oxidative distress. As normal cells have a greater capacity to meet oxidative challenges than tumor cells, increasing the flux of oxidants with high dose selenium treatment could result in cancer-specific cell killing. If the availability of Se is limited, supplementation of Se can increase the expression and activities of Se-dependent proteins and enzymes. In cell culture, selenium deficiency is often overlooked. We review the importance of achieving normal selenium biology and how Se deficiency can lead to adverse effects. We examine the vital role of selenium in the prevention and treatment of cancer. Finally, we examine the properties of Se-compounds to better understand how each can be used to address different research questions.

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Role of Nuclei in Liesegang Pattern Formation: Insights from Experiment and Reaction-Diffusion Simulation

The Journal of Physical Chemistry C ◽

10.1021/acs.jpcc.7b12688 ◽

2018 ◽

Vol 122 (6) ◽

pp. 3669-3676 ◽

Cited By ~ 5

Author(s):

Masaki Itatani ◽

Qing Fang ◽

Kei Unoura ◽

Hideki Nabika

Keyword(s):

Pattern Formation ◽

Reaction Diffusion ◽

Diffusion Simulation

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Differential Pathways of Angiotensin II-Induced Extracellularly Regulated Kinase 1/2 Phosphorylation in Specific Cell Types: Role of Heparin-Binding Epidermal Growth Factor

Molecular Endocrinology ◽

10.1210/me.2003-0476 ◽

2004 ◽

Vol 18 (8) ◽

pp. 2035-2048 ◽

Cited By ~ 62

Author(s):

Bukhtiar H. Shah ◽

Akin Yesilkaya ◽

J. Alberto Olivares-Reyes ◽

Hung-Dar Chen ◽

László Hunyady ◽

...

Keyword(s):

Angiotensin Ii ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Types ◽

Specific Cell ◽

Heparin Binding ◽

Epidermal Growth

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Citral, an inhibitor of retinoic acid synthesis, modifies pattern formation during limb regeneration in the axolotl Ambystoma mexicanum

Canadian Journal of Zoology ◽

10.1139/z99-147 ◽

1999 ◽

Vol 77 (11) ◽

pp. 1835-1837 ◽

Cited By ~ 8

Author(s):

Steven R Scadding

Keyword(s):

Retinoic Acid ◽

Pattern Formation ◽

Limb Regeneration ◽

Acid Synthesis ◽

Ambystoma Mexicanum

While the effects of exogenous retinoids on amphibian limb regeneration have been studied extensively, the role of endogenous retinoids is not clear. Hence, I wished to investigate the role of endogenous retinoic acid during axolotl limb regeneration. Citral is a known inhibitor of retinoic acid synthesis. Thus, I treated regenerating limbs of the larval axolotl Ambystoma mexicanum with citral. The result of this inhibition of retinoic acid synthesis was that limb regeneration became extremely irregular and hypomorphic, with serious pattern defects, or was inhibited altogether. I conclude that endogenous retinoic acid plays an important role in pattern formation during limb regeneration.

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‘Generic’ physical mechanisms of morphogenesis and pattern formation

Development ◽

10.1242/dev.110.1.1 ◽

1990 ◽

Vol 110 (1) ◽

pp. 1-18 ◽

Cited By ~ 14

Author(s):

S.A. Newman ◽

W.D. Comper

Keyword(s):

Pattern Formation ◽

Reaction Diffusion ◽

Physical Mechanisms ◽

Extracellular Matrix Components ◽

Genetic Mechanisms ◽

Chemical Waves ◽

Phylogenetic Lineages ◽

Living Tissues ◽

Highly Evolved

The role of ‘generic’ physical mechanisms in morphogenesis and pattern formation of tissues is considered. Generic mechanisms are defined as those physical processes that are broadly applicable to living and non-living systems, such as adhesion, surface tension and gravitational effects, viscosity, phase separation, convection and reaction-diffusion coupling. They are contrasted with ‘genetic’ mechanisms, a term reserved for highly evolved, machine-like, biomolecular processes. Generic mechanisms acting upon living tissues are capable of giving rise to morphogenetic rearrangements of cytoplasmic, tissue and extracellular matrix components, sometimes leading to ‘microfingers’, and to chemical waves or stripes. We suggest that many morphogenetic and patterning effects are the inevitable outcome of recognized physical properties of tissues, and that generic physical mechanisms that act on these properties are complementary to, and interdependent with genetic mechanisms. We also suggest that major morphological reorganizations in phylogenetic lineages may arise by the action of generic physical mechanisms on developing embryos. Subsequent evolution of genetic mechanisms could stabilize and refine developmental outcomes originally guided by generic effects.

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Regulated expression of a murine class I gene in transgenic mice

Molecular and Cellular Biology ◽

10.1128/mcb.6.4.1339-1342.1986 ◽

1986 ◽

Vol 6 (4) ◽

pp. 1339-1342

Author(s):

C Bieberich ◽

G Scangos ◽

K Tanaka ◽

G Jay

Keyword(s):

Transgenic Mice ◽

Germ Line ◽

Inbred Mice ◽

Class I ◽

Endogenous Gene ◽

Histocompatibility Complex ◽

Unique System ◽

Regulated Expression ◽

I Gene

The major histocompatibility complex class I genes play an essential role in the immune presentation of aberrant cells. To gain further insight into the regulation of the expression of these class I genes and to better define the functions of their protein products, we made use of the technique of gene transfer into the germ line of inbred mice. With the use of locus-specific DNA probes, we observed that a transgenic class I gene was expressed in a tissue-dependent fashion analogous to that of an endogenous class I gene. In addition, the level of expression of the transgenic gene was substantially higher that that of the endogenous gene. The availability of transgenic mice properly expressing a foreign murine class I gene provides a unique system to further define the role of the class I antigens in the maturation of the immune response and in determining the malignant and metastatic phenotypes of tumor cells.

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Molecular Markers in Upper Urothelial Carcinoma Associated to Balkan Endemic Nephropathy. Aristolochic Acid as the Major Risk Factor of the Worldwide Disease

The Scientific World JOURNAL ◽

10.1100/tsw.2009.162 ◽

2009 ◽

Vol 9 ◽

pp. 1360-1373 ◽

Cited By ~ 8

Author(s):

Ljubinka Jankovic Velickovic ◽

Takanori Hattori ◽

Vladisav Stefanovic

Keyword(s):

Regression Analysis ◽

Urothelial Carcinoma ◽

Growth Stage ◽

Aristolochic Acid ◽

Balkan Endemic Nephropathy ◽

Specific Cell ◽

Ki 67 ◽

High Stage ◽

Endemic Nephropathy

The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper urothelial carcinoma (UUC) was recently confirmed. The aim of this study was to determine the marker(s) specific for BEN-associated UUC. A total of 82 patients with UUC (38 from the BEN region and 44 control tumors) were included in the study. The Ki-67 index in BEN tumors correlated with the grade and multifocality (p< 0.05), but in regression analysis, only the grade of BEN tumor. The p53 index was significantly higher in BEN than in control tumors (p< 0.05), as well as the alteration of p53 (p< 0.05). BEN low-stage tumors, tumors without limphovascular invasion (LVI), and tumors of the renal pelvis had a higher p53 index than the control tumors (p< 0.05, 0.01, 0.05, respectively). The Ki-67 index was higher in control tumors with high-stage and solid growth than in BEN UUC (p < 0.050, 0.005). The Ki-67 correlated with the grade, growth, stage, LVI, and multifocality of UUC on the best way, but not with the group. In regression analysis, only multifocality of UUC had predictive influence on Ki-67 activity (p< 0.001). P53 correlated with the grade, growth, and group (p< 0.05). This investigation identifies the p53 pathway as the specific cell cycle marker involved in BEN-associated UUC.

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Comprehensive Genomic Discovery of Non-Coding Transcriptional Enhancers in the African Malaria Vector Anopheles coluzzii

Frontiers in Genetics ◽

10.3389/fgene.2021.785934 ◽

2022 ◽

Vol 12 ◽

Author(s):

Inge Holm ◽

Luisa Nardini ◽

Adrien Pain ◽

Emmanuel Bischoff ◽

Cameron E. Anderson ◽

...

Keyword(s):

Malaria Vector ◽

Regulatory Elements ◽

Specific Cell ◽

Insect Vector ◽

Anopheles Coluzzii ◽

Gene Promoters ◽

Transcriptional Enhancers ◽

Genome Wide ◽

A Genome

Almost all regulation of gene expression in eukaryotic genomes is mediated by the action of distant non-coding transcriptional enhancers upon proximal gene promoters. Enhancer locations cannot be accurately predicted bioinformatically because of the absence of a defined sequence code, and thus functional assays are required for their direct detection. Here we used a massively parallel reporter assay, Self-Transcribing Active Regulatory Region sequencing (STARR-seq), to generate the first comprehensive genome-wide map of enhancers in Anopheles coluzzii, a major African malaria vector in the Gambiae species complex. The screen was carried out by transfecting reporter libraries created from the genomic DNA of 60 wild A. coluzzii from Burkina Faso into A. coluzzii 4a3A cells, in order to functionally query enhancer activity of the natural population within the homologous cellular context. We report a catalog of 3,288 active genomic enhancers that were significant across three biological replicates, 74% of them located in intergenic and intronic regions. The STARR-seq enhancer screen is chromatin-free and thus detects inherent activity of a comprehensive catalog of enhancers that may be restricted in vivo to specific cell types or developmental stages. Testing of a validation panel of enhancer candidates using manual luciferase assays confirmed enhancer function in 26 of 28 (93%) of the candidates over a wide dynamic range of activity from two to at least 16-fold activity above baseline. The enhancers occupy only 0.7% of the genome, and display distinct composition features. The enhancer compartment is significantly enriched for 15 transcription factor binding site signatures, and displays divergence for specific dinucleotide repeats, as compared to matched non-enhancer genomic controls. The genome-wide catalog of A. coluzzii enhancers is publicly available in a simple searchable graphic format. This enhancer catalogue will be valuable in linking genetic and phenotypic variation, in identifying regulatory elements that could be employed in vector manipulation, and in better targeting of chromosome editing to minimize extraneous regulation influences on the introduced sequences.Importance: Understanding the role of the non-coding regulatory genome in complex disease phenotypes is essential, but even in well-characterized model organisms, identification of regulatory regions within the vast non-coding genome remains a challenge. We used a large-scale assay to generate a genome wide map of transcriptional enhancers. Such a catalogue for the important malaria vector, Anopheles coluzzii, will be an important research tool as the role of non-coding regulatory variation in differential susceptibility to malaria infection is explored and as a public resource for research on this important insect vector of disease.

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