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1.
MicroPubl Biol ; 20242024.
Artículo en Inglés | MEDLINE | ID: mdl-38764944

RESUMEN

Lifespan studies on fast-aging model organisms like C.elegans and D.melanogaster are conducted with multiple organisms per vial. Lifespan data results in a "one row, multiple individuals" format, which is incompatible with R packages that require a "one row, one individual" format. We present ggbulksurv , an R package for user-friendly survival analysis and highlight three key features. (1) pivot_prism converts data for PRISM, allowing biologists to plot survival curves without manually expanding each observation. (2) run_bulksurv() takes in a "one row, multiple individuals" table and plots a customizable survival curve. (3) Advanced users who require custom survival objects can specify a custom formula, facilitating complex survival analysis. We provide a time saving solution for lifespan data analysis.

2.
J Dev Biol ; 12(2)2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38804435

RESUMEN

In this Special Issue, titled "Drosophila-A Model System for Developmental Biology", we present a series of articles and reviews looking at the diverse ways that researchers are using the humble fruit fly, also known as the vinegar fly, to tackle the many aspects of development and homeostasis [...].

3.
Cells ; 13(5)2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38474329

RESUMEN

Wnt signaling is a highly conserved metazoan pathway that plays a crucial role in cell fate determination and morphogenesis during development. Wnt ligands can induce disparate cellular responses. The exact mechanism behind these different outcomes is not fully understood but may be due to interactions with different receptors on the cell membrane. PTK7/Otk is a transmembrane receptor that is implicated in various developmental and physiological processes including cell polarity, cell migration, and invasion. Here, we examine two roles of Otk-1 and Otk-2 in patterning and neurogenesis. We find that Otk-1 is a positive regulator of signaling and Otk-2 functions as its inhibitor. We propose that PTK7/Otk functions in signaling, cell migration, and polarity contributing to the diversity of cellular responses seen in Wnt-mediated processes.


Asunto(s)
Tipificación del Cuerpo , Neurogénesis , Proteínas Tirosina Quinasas Receptoras , Vía de Señalización Wnt , Animales , Diferenciación Celular , Membrana Celular/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Vía de Señalización Wnt/fisiología
4.
Int J Mol Sci ; 24(5)2023 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-36901729

RESUMEN

Across the world a dementia case is diagnosed every three seconds. Alzheimer's disease (AD) causes 50-60% of these cases. The most prominent theory for AD correlates the deposition of amyloid beta (Aß) with the onset of dementia. Whether Aß is causative remains unclear due to findings such as the recently approved drug Aducanumab showing effective clearance of Aß, but not improving cognition. New approaches for understanding Aß function, are therefore necessary. Here we discuss the application of optogenetic techniques to gain insight into AD. Optogenetics, or genetically encoded, light-dependent on/off switches, provides precise spatiotemporal control to regulate cellular dynamics. This precise control over protein expression and oligomerization or aggregation could provide a better understanding of the etiology of AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Cognición , Optogenética , Procesamiento Proteico-Postraduccional
5.
J Cell Sci ; 135(21)2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36217793

RESUMEN

The gene mutated in colorectal cancer (MCC) encodes a coiled-coil protein implicated, as its name suggests, in the pathogenesis of hereditary human colon cancer. To date, however, the contributions of MCC to intestinal homeostasis and disease remain unclear. Here, we examine the subcellular localization of MCC, both at the mRNA and protein levels, in the adult intestinal epithelium. Our findings reveal that Mcc transcripts are restricted to proliferating crypt cells, including Lgr5+ stem cells, where the Mcc protein is distinctly associated with the centrosome. Upon intestinal cellular differentiation, Mcc is redeployed to the apical domain of polarized villus cells where non-centrosomal microtubule organizing centers (ncMTOCs) are positioned. Using intestinal organoids, we show that the shuttling of the Mcc protein depends on phosphorylation by casein kinases 1δ and ε, which are critical modulators of WNT signaling. Together, our findings support a role for MCC in establishing and maintaining the cellular architecture of the intestinal epithelium as a component of both the centrosome and ncMTOC.


Asunto(s)
Centrosoma , Centro Organizador de los Microtúbulos , Humanos , Centro Organizador de los Microtúbulos/metabolismo , Centrosoma/metabolismo , Intestinos , Diferenciación Celular , Proteínas/metabolismo , Mucosa Intestinal/metabolismo
6.
Aging (Albany NY) ; 14(20): 8270-8291, 2022 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-36287172

RESUMEN

Why biological age is a major risk factor for many of the most important human diseases remains mysterious. We know that as organisms age, stem cell pools are exhausted while senescent cells progressively accumulate. Independently, induction of pluripotency via expression of Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) and clearance of senescent cells have each been shown to ameliorate cellular and physiological aspects of aging, suggesting that both processes are drivers of organismal aging. But stem cell exhaustion and cellular senescence likely interact in the etiology and progression of age-dependent diseases because both undermine tissue and organ homeostasis in different if not complementary ways. Here, we combine transient cellular reprogramming (stem cell rejuvenation) with targeted removal of senescent cells to test the hypothesis that simultaneously targeting both cell-fate based aging mechanisms will maximize life and health span benefits. We find that OKSM extends lifespan and show that both interventions protect the intestinal stem cell pool, lower inflammation, activate pro-stem cell signaling pathways, and synergistically improve health and lifespan. Our findings suggest that a combination therapy, simultaneously replacing lost stem cells and removing senescent cells, shows synergistic potential for anti-aging treatments. Our finding that transient expression of both is the most effective suggests that drug-based treatments in non-genetically tractable organisms will likely be the most translatable.


Asunto(s)
Longevidad , Rejuvenecimiento , Humanos , Longevidad/fisiología , Rejuvenecimiento/fisiología , Senescencia Celular/fisiología , Envejecimiento/fisiología , Células Madre
7.
Sci Rep ; 12(1): 7684, 2022 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-35538124

RESUMEN

Proper embryonic development requires directional axes to pattern cells into embryonic structures. In Drosophila, spatially discrete expression of transcription factors determines the anterior to posterior organization of the early embryo, while the Toll and TGFß signalling pathways determine the early dorsal to ventral pattern. Embryonic MAPK/ERK signaling contributes to both anterior to posterior patterning in the terminal regions and to dorsal to ventral patterning during oogenesis and embryonic stages. Here we describe a novel loss of function mutation in the Raf kinase gene, which leads to loss of ventral cell fates as seen through the loss of the ventral furrow, the absence of Dorsal/NFκB nuclear localization, the absence of mesoderm determinants Twist and Snail, and the expansion of TGFß. Gene expression analysis showed cells adopting ectodermal fates much like loss of Toll signaling. Our results combine novel mutants, live imaging, optogenetics and transcriptomics to establish a novel role for Raf, that appears to be independent of the MAPK cascade, in embryonic patterning.


Asunto(s)
Proteínas de Drosophila , Drosophila , Animales , Tipificación del Cuerpo/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Oogénesis , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
8.
Cells ; 11(2)2022 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-35053396

RESUMEN

Patients with Alzheimer's disease suffer from a decrease in brain mass and a prevalence of amyloid-ß plaques. These plaques are thought to play a role in disease progression, but their exact role is not entirely established. We developed an optogenetic model to induce amyloid-ß intracellular oligomerization to model distinct disease etiologies. Here, we examine the effect of Wnt signaling on amyloid in an optogenetic, Drosophila gut stem cell model. We observe that Wnt activation rescues the detrimental effects of amyloid expression and oligomerization. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find changes in aging related genes, protein misfolding, metabolism, and inflammation. We propose that Wnt expression reduces inflammation through repression of Toll activating factors. We confirm that chronic Toll activation reduces lifespan, but a decrease in the upstream activator Persephone extends it. We propose that the protective effect observed for lithium treatment functions, at least in part, through Wnt activation and the inhibition of inflammation.


Asunto(s)
Péptidos beta-Amiloides/toxicidad , Drosophila melanogaster/metabolismo , Intestinos/patología , Células Madre/patología , Vía de Señalización Wnt , Animales , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/embriología , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Longevidad/efectos de los fármacos , Optogenética , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/genética
9.
Cell Mol Life Sci ; 78(16): 5865-5880, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34232330

RESUMEN

Many organs and tissues have an intrinsic ability to regenerate from a dedicated, tissue-specific stem cell pool. As organisms age, the process of self-regulation or homeostasis begins to slow down with fewer stem cells available for tissue repair. Tissues become more fragile and organs less efficient. This slowdown of homeostatic processes leads to the development of cellular and neurodegenerative diseases. In this review, we highlight the recent use and future potential of optogenetic approaches to study homeostasis. Optogenetics uses photosensitive molecules and genetic engineering to modulate cellular activity in vivo, allowing precise experiments with spatiotemporal control. We look at applications of this technology for understanding the mechanisms governing homeostasis and degeneration as applied to widely used model organisms, such as Drosophila melanogaster, where other common tools are less effective or unavailable.


Asunto(s)
Drosophila melanogaster/genética , Homeostasis/genética , Regeneración/genética , Animales , Humanos , Optogenética/métodos , Transducción de Señal/genética , Células Madre/fisiología , Cicatrización de Heridas/genética
10.
FEBS J ; 288(12): 3855-3873, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32853472

RESUMEN

'A peculiar severe disease process of the cerebral cortex' are the exact words used by A. Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD etiology have emerged throughout the past century. In this review, we focus on the metabolic mechanisms that are similar between AD and metabolic diseases, based on the results from genome-wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Corteza Cerebral/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Transducción de Señal/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Metformina/uso terapéutico , Optogenética/métodos , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Compuestos de Sulfonilurea/uso terapéutico , Proteínas tau/genética , Proteínas tau/metabolismo
11.
Elife ; 92020 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-32228858

RESUMEN

The brains of Alzheimer's disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-ß plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-ß plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer's disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-ß peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-ß oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-ß peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-ß oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-ß were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-ß oligomerization from Amyloid-ß expression alone. The physical damage caused by Amyloid-ß oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-ß oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.


Alzheimer's disease is a progressive condition that damages the brain over time. The cause is not clear, but a toxic molecule called Amyloid-ß peptide seems to play a part. It builds up in the brains of people with Alzheimer's disease, forming hard clumps called plaques. Yet, though the plaques are a hallmark of the disease, experimental treatments designed to break them down do not seem to help. This raises the question ­ do Amyloid-ß plaques actually cause Alzheimer's disease? Answering this question is not easy. One way to study the effect of amyloid plaques is to inject clumps of Amyloid-ß peptides into model organisms. This triggers Alzheimer's-like brain damage, but it is not clear why. It remains difficult to tell the difference between the damage caused by the injected Amyloid-ß peptides and the damage caused by the solid plaques that they form. For this, researchers need a way to trigger plaque formation directly inside animal brains. This would make it possible to test the effects of plaque-targeting treatments, like the drug lithium. Optogenetics is a technique that uses light to control molecules in living animals. Hsien, Kaur et al. have now used this approach to trigger plaque formation by fusing light-sensitive proteins to Amyloid-ß peptides in worms, fruit flies and zebrafish. This meant that the peptides clumped together to form plaques whenever the animals were exposed to blue light. This revealed that, while both the Amyloid-ß peptides and the plaques caused damage, the plaques were much more toxic. They damaged cell metabolism and caused tissue loss that resembled late Alzheimer's disease in humans. To find out whether it was possible to test Alzheimer's treatments in these animals, Hsien, Kaur et al. treated them with the drug, lithium. This increased their lifespan, reversing some of the damage caused by the plaques. Alzheimer's disease affects more than 46.8 million people worldwide and is the sixth leading cause of death in the USA. But, despite over 50 years of research, there is no cure. This new plaque-formation technique allows researchers to study the effects of amyloid plaques in living animals, providing a new way to test Alzheimer's treatments. This could be of particular help in studies of experimental drugs that aim to reduce plaque formation.


Asunto(s)
Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/fisiopatología , Luz , Optogenética/métodos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/efectos de la radiación , Caenorhabditis elegans , Progresión de la Enfermedad , Drosophila , Femenino , Células HEK293 , Humanos , Litio/administración & dosificación , Masculino , Enfermedades Neurodegenerativas , Placa Amiloide , Pez Cebra
12.
J Mol Biol ; 432(10): 3159-3176, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32201167

RESUMEN

Homeostasis in adult organs involves replacement of cells from a stem cell pool maintained in specialized niches regulated by extracellular signals. This cell-to-cell communication employs signal transduction pathways allowing cells to respond with a variety of behaviors. To study these cellular behaviors, signaling must be perturbed within tissues in precise patterns, a technique recently made possible by the development of optogenetic tools. We developed tools to study signal transduction in vivo in an adult fly midgut stem cell model where signaling was regulated by the application of light. Activation was achieved by clustering of membrane receptors EGFR and Toll, while inactivation was achieved by clustering the downstream activators ERK/Rolled and NFκB/Dorsal in the cytoplasm, preventing nuclear translocation and transcriptional activation. We show that both pathways contribute to stem and transit amplifying cell numbers and affect the lifespan of adult flies. We further present new approaches to overcome overexpression phenotypes and novel methods for the integration of optogenetics into the already-established genetic toolkit of Drosophila.


Asunto(s)
Drosophila melanogaster/crecimiento & desarrollo , Redes Reguladoras de Genes , Mucosa Intestinal/citología , Optogenética/métodos , Animales , Comunicación Celular , Proliferación Celular , Células Cultivadas , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Homeostasis , Mucosa Intestinal/metabolismo , Luz , Longevidad , Transducción de Señal , Células Madre/citología , Células Madre/metabolismo
13.
Cells ; 8(8)2019 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-31382613

RESUMEN

Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. Here, we discuss the WNT pathway and its role in human disease and some of the advances in WNT-related treatments.


Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedades Metabólicas/metabolismo , Neoplasias/metabolismo , Vía de Señalización Wnt , Desarrollo Embrionario/fisiología , Humanos
14.
Dev Cell ; 47(1): 67-79.e5, 2018 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-30269951

RESUMEN

There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-ß pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits.


Asunto(s)
Envejecimiento/efectos de los fármacos , Longevidad/efectos de los fármacos , Alantoína , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Drosophila melanogaster/efectos de los fármacos , Sinergismo Farmacológico , Ficusina , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Metabolismo de los Lípidos , Lípidos , Longevidad/genética , Metformina , Rifampin , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sirolimus , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Transcriptoma , Factor de Crecimiento Transformador beta/metabolismo
15.
Genes (Basel) ; 9(2)2018 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-29462894

RESUMEN

The discovery of induced pluripotent stem (iPS) cells, barely more than a decade ago, dramatically transformed the study of stem cells and introduced a completely new way to approach many human health concerns. Although advances have pushed the field forward, human application remains some years away, in part due to the need for an in-depth mechanistic understanding. The role of Wnts in stem cells predates the discovery of iPS cells with Wnts established as major pluripotency promoting factors. Most work to date has been done using mouse and tissue culture models and few attempts have been made in other model organisms, but the recent combination of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing with iPS cell technology provides a perfect avenue for exploring iPS cells in model organisms. Drosophila is an ideal organism for such studies, but fly iPS cells have not yet been made. In this opinion article, we draw parallels between Wnt signaling in human and Drosophila stem cell systems, propose ways to obtain Drosophila iPS cells, and suggest ways to exploit the versatility of the Drosophila system for future stem cell studies.

16.
Sci Rep ; 7(1): 16636, 2017 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-29192250

RESUMEN

Optogenetics allows precise, fast and reversible intervention in biological processes. Light-sheet microscopy allows observation of the full course of Drosophila embryonic development from egg to larva. Bringing the two approaches together allows unparalleled precision into the temporal regulation of signaling pathways and cellular processes in vivo. To develop this method, we investigated the regulation of canonical Wnt signaling during anterior-posterior patterning of the Drosophila embryonic epidermis. Cryptochrome 2 (CRY2) from Arabidopsis Thaliana was fused to mCherry fluorescent protein and Drosophila ß-catenin to form an easy to visualize optogenetic switch. Blue light illumination caused oligomerization of the fusion protein and inhibited downstream Wnt signaling in vitro and in vivo. Temporal inactivation of ß-catenin confirmed that Wnt signaling is required not only for Drosophila pattern formation, but also for maintenance later in development. We anticipate that this method will be easily extendable to other developmental signaling pathways and many other experimental systems.


Asunto(s)
Desarrollo Embrionario , Microscopía , Optogenética , Vía de Señalización Wnt , Arabidopsis , Criptocromos/química , Criptocromos/metabolismo , Luz , Microscopía/métodos , Imagen Molecular , Mutación , Optogenética/métodos , beta Catenina/química , beta Catenina/metabolismo
17.
Sci Rep ; 7(1): 11092, 2017 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-28894169

RESUMEN

During animal development, complex signals determine and organize a vast number of tissues using a very small number of signal transduction pathways. These developmental signaling pathways determine cell fates through a coordinated transcriptional response that remains poorly understood. The Wnt pathway is involved in a variety of these cellular functions, and its signals are transmitted in part through a ß-catenin/TCF transcriptional complex. Here we report an in vivo Drosophila assay that can be used to distinguish between activation, de-repression and repression of transcriptional responses, separating upstream and downstream pathway activation and canonical/non-canonical Wnt signals in embryos. We find specific sets of genes downstream of both ß-catenin and TCF with an additional group of genes regulated by Wnt, while the non-canonical Wnt4 regulates a separate cohort of genes. We correlate transcriptional changes with phenotypic outcomes of cell differentiation and embryo size, showing our model can be used to characterize developmental signaling compartmentalization in vivo.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Activación Transcripcional , Proteínas Wnt/metabolismo , Animales , Apoptosis , Biología Computacional/métodos , Drosophila/embriología , Drosophila/metabolismo , Perfilación de la Expresión Génica , Ontología de Genes , Mutación , Fenotipo , Unión Proteica , Transcriptoma , Vía de Señalización Wnt
18.
Sci Rep ; 7(1): 6934, 2017 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-28761148

RESUMEN

The highly conserved Wnt signaling pathway regulates cell proliferation and differentiation in vertebrates and invertebrates. Upon binding of a Wnt ligand to a receptor of the Fz family, Disheveled (Dsh/Dvl) transduces the signal during canonical and non-canonical Wnt signaling. The specific details of how this process occurs have proven difficult to study, especially as Dsh appears to function as a switch between different branches of Wnt signaling. Here we focus on the membrane-proximal events that occur once Dsh is recruited to the membrane. We show that membrane-tethering of the Dsh protein is sufficient to induce canonical Wnt signaling activation even in the absence of the Wnt co-receptor Arrow/LRP5/6. We map the protein domains required for pathway activation in membrane tethered constructs finding that both the DEP and PDZ domains are dispensable for canonical signaling only in membrane-tethered Dsh, but not in untethered/normal Dsh. These data lead to a signal activation model, where Arrow is required to localize Dsh to the membrane during canonical Wnt signaling placing Dsh downstream of Arrow.


Asunto(s)
Membrana Celular/metabolismo , Proteínas Dishevelled/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Sitios de Unión , Proteínas Dishevelled/química , Proteínas Dishevelled/genética , Drosophila/embriología , Drosophila/genética , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Femenino , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Dominios Proteicos , Receptores de Superficie Celular/genética , Vía de Señalización Wnt
19.
Br J Pharmacol ; 174(24): 4684-4700, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28736855

RESUMEN

Recent discoveries in the non-coding genome have challenged the original central dogma of molecular biology, as non-coding RNAs and related processes have been found to be important in regulating gene expression. MicroRNAs and long non-coding RNAs (lncRNAs) are among those that have gained attention recently in human diseases, including cancer, with the involvement of many more non-coding RNAs (ncRNAs) waiting to be discovered. ncRNAs are a group of ribonucleic acids transcribed from regions of the human genome, which do not become translated into proteins, despite having essential roles in cellular physiology. Deregulation of ncRNA expression and function has been observed in cancer pathogenesis. Recently, the roles of a group of ncRNA known as lncRNA have gained attention in cancer, with increasing reports of their oncogenic involvement. Female reproductive cancers remain a leading cause of death in the female population, accounting for almost a third of all female cancer deaths in 2016. The Wnt signalling pathway is one of the most important oncogenic signalling pathways which is hyperactivated in cancers, including female reproductive cancers. The extension of ncRNA research into their mechanistic roles in human cancers has also led to novel reported roles of ncRNAs in the Wnt pathway and Wnt-mediated oncogenesis. This review aims to provide a critical summary of the respective roles and cellular functions of Wnt-associated lncRNAs in female reproductive cancers and explores the potential of circulating cell-free lncRNAs as diagnostic markers and lncRNAs as therapeutic targets. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.


Asunto(s)
MicroARNs/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , ARN Largo no Codificante/genética , ARN Largo no Codificante/uso terapéutico , Vía de Señalización Wnt/genética , Femenino , Humanos
20.
Elife ; 62017 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-28691901

RESUMEN

Morphogen gradients provide essential spatial information during development. Not only the local concentration but also duration of morphogen exposure is critical for correct cell fate decisions. Yet, how and when cells temporally integrate signals from a morphogen remains unclear. Here, we use optogenetic manipulation to switch off Bicoid-dependent transcription in the early Drosophila embryo with high temporal resolution, allowing time-specific and reversible manipulation of morphogen signalling. We find that Bicoid transcriptional activity is dispensable for embryonic viability in the first hour after fertilization, but persistently required throughout the rest of the blastoderm stage. Short interruptions of Bicoid activity alter the most anterior cell fate decisions, while prolonged inactivation expands patterning defects from anterior to posterior. Such anterior susceptibility correlates with high reliance of anterior gap gene expression on Bicoid. Therefore, cell fates exposed to higher Bicoid concentration require input for longer duration, demonstrating a previously unknown aspect of Bicoid decoding.


Asunto(s)
Drosophila/embriología , Proteínas de Homeodominio/metabolismo , Transactivadores/metabolismo , Animales , Tipificación del Cuerpo , Proteínas de Drosophila , Optogenética , Análisis de Supervivencia , Factores de Tiempo
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