Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 73
Filtrar
1.
Nature ; 602(7896): 287-293, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34937053

RESUMO

Morphogen gradients are fundamental to establish morphological patterns in developing tissues1. During development, gradients scale to remain proportional to the size of growing organs2,3. Scaling is a universal gear that adjusts patterns to size in living organisms3-8, but its mechanisms remain unclear. Here, focusing on the Decapentaplegic (Dpp) gradient in the Drosophila wing disc, we uncover a cell biological basis behind scaling. From small to large discs, scaling of the Dpp gradient is achieved by increasing the contribution of the internalized Dpp molecules to Dpp transport: to expand the gradient, endocytosed molecules are re-exocytosed to spread extracellularly. To regulate the contribution of endocytosed Dpp to the spreading extracellular pool during tissue growth, it is the Dpp binding rates that are progressively modulated by the extracellular factor Pentagone, which drives scaling. Thus, for some morphogens, evolution may act on endocytic trafficking to regulate the range of the gradient and its scaling, which could allow the adaptation of shape and pattern to different sizes of organs in different species.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Endocitose , Morfogênese , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
2.
Nat Rev Mol Cell Biol ; 12(9): 594-604, 2011 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-21850035

RESUMO

Morphogens are secreted signalling molecules that control the patterning and growth of developing organs. How morphogens regulate patterning is fairly well understood; however, how they control growth is less clear. Four principal models have been proposed to explain how the morphogenetic protein Decapentaplegic (DPP) controls the growth of the wing imaginal disc in the fly. Recent studies in this model system have provided a wealth of experimental data on growth and DPP gradient properties, as well as on the interactions of DPP with other signalling pathways. These findings have allowed a more precise formulation and evaluation of morphogenetic growth models. The insights into growth control by the DPP gradient will also be useful for understanding other morphogenetic growth systems.


Assuntos
Dípteros/crescimento & desenvolvimento , Crescimento/fisiologia , Morfogênese/genética , Animais , Compreensão , Dípteros/embriologia , Dípteros/fisiologia , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/fisiologia , Crescimento/genética , Humanos , Modelos Biológicos , Morfogênese/fisiologia
3.
Proc Natl Acad Sci U S A ; 117(28): 16292-16301, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601208

RESUMO

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.


Assuntos
Receptores Notch/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Drosophila , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/química , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Camundongos , Mutação , Fenótipo , Multimerização Proteica , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
4.
Nature ; 528(7581): 280-5, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26659188

RESUMO

During asymmetric division, fate determinants at the cell cortex segregate unequally into the two daughter cells. It has recently been shown that Sara (Smad anchor for receptor activation) signalling endosomes in the cytoplasm also segregate asymmetrically during asymmetric division. Biased dispatch of Sara endosomes mediates asymmetric Notch/Delta signalling during the asymmetric division of sensory organ precursors in Drosophila. In flies, this has been generalized to stem cells in the gut and the central nervous system, and, in zebrafish, to neural precursors of the spinal cord. However, the mechanism of asymmetric endosome segregation is not understood. Here we show that the plus-end kinesin motor Klp98A targets Sara endosomes to the central spindle, where they move bidirectionally on an antiparallel array of microtubules. The microtubule depolymerizing kinesin Klp10A and its antagonist Patronin generate central spindle asymmetry. This asymmetric spindle, in turn, polarizes endosome motility, ultimately causing asymmetric endosome dispatch into one daughter cell. We demonstrate this mechanism by inverting the polarity of the central spindle by polar targeting of Patronin using nanobodies (single-domain antibodies). This spindle inversion targets the endosomes to the wrong cell. Our data uncover the molecular and physical mechanism by which organelles localized away from the cellular cortex can be dispatched asymmetrically during asymmetric division.


Assuntos
Divisão Celular Assimétrica/fisiologia , Drosophila melanogaster/citologia , Endossomos/metabolismo , Cinesinas/metabolismo , Fuso Acromático/fisiologia , Animais , Polaridade Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Cinesinas/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Deleção de Sequência , Anticorpos de Domínio Único
5.
Chimia (Aarau) ; 75(12): 1004-1011, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34920768

RESUMO

This article describes four fluorescent membrane tension probes that have been designed, synthesized, evaluated, commercialized and applied to current biology challenges in the context of the NCCR Chemical Biology. Their names are Flipper-TR®, ER Flipper-TR®, Lyso Flipper-TR®, and Mito Flipper-TR®. They are available from Spirochrome.


Assuntos
Corantes Fluorescentes , Potencial da Membrana Mitocondrial , Corantes , Microscopia de Fluorescência
6.
J Am Chem Soc ; 142(10): 4784-4792, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32109058

RESUMO

In this report, cell-penetrating streptavidin (CPS) is introduced to exploit the full power of streptavidin-biotin biotechnology in cellular uptake. For this purpose, transporters, here cyclic oligochalcogenides (COCs), are covalently attached to lysines of wild-type streptavidin. This leaves all four biotin binding sites free for at least bifunctional delivery. To maximize the standards of the quantitative evaluation of cytosolic delivery, the recent chloroalkane penetration assay (CAPA) is coupled with automated high content (HC) imaging, a technique that combines the advantages of fluorescence microscopy and flow cytometry. According to the resulting HC-CAPA, cytosolic delivery of CPS equipped with four benzopolysulfanes was the best among all tested CPSs, also better than the much smaller TAT peptide, the original cell-penetrating peptide from HIV. HaloTag-GFP fusion proteins expressed on mitochondria were successfully targeted using CPS carrying two different biotinylated ligands, HaloTag substrates or anti-GFP nanobodies, interfaced with peptide nucleic acids, flipper force probes, or fluorescent substrates. The delivered substrates could be released from CPS into the cytosol through desthiobiotin-biotin exchange. These results validate CPS as a general tool which enables unrestricted use of streptavidin-biotin biotechnology in cellular uptake.


Assuntos
Biotina/metabolismo , Peptídeos Penetradores de Células/metabolismo , Sistemas de Liberação de Medicamentos , Estreptavidina/metabolismo , Sulfetos/metabolismo , Biotina/química , Peptídeos Penetradores de Células/síntese química , Corantes Fluorescentes/química , Células HeLa , Humanos , Microscopia de Fluorescência , Ácidos Nucleicos Peptídicos/química , Anticorpos de Domínio Único/química , Estreptavidina/química , Sulfetos/síntese química
7.
Chemistry ; 25(16): 4047-4051, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30815941

RESUMO

Cyclic oligochalcogenides are emerging as powerful tools to penetrate cells. With disulfide ring tension maximized, selenium chemistry had to be explored next to enhance speed and selectivity of dynamic covalent exchange on the way into the cytosol. We show that diseleno lipoic acid (DiSeL) delivers a variety of relevant substrates. DiSeL-driven uptake of artificial metalloenzymes enables bioorthogonal fluorophore uncaging within cells. Binding of a bicyclic peptide, phalloidin, to actin fibers evinces targeted delivery to the cytosol. Automated tracking of diffusive compared to directed motility and immobility localizes 79 % of protein-coated quantum dots (QDs) in the cytosol, with little endosomal capture (0.06 %). These results suggest that diselenolanes might act as molecular walkers along disulfide tracks in locally denatured membrane proteins, surrounded by adaptive micellar membrane defects. Miniscule and versatile, DiSeL tags are also readily available, stable, soluble, and non-toxic.


Assuntos
Peptídeos Penetradores de Células/química , Citosol/química , Metaloproteínas/química , Pontos Quânticos/química , Compostos de Selênio/metabolismo , Actinas/metabolismo , Sequência de Aminoácidos , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Difusão , Corantes Fluorescentes/química , Modelos Moleculares , Imagem Óptica/métodos , Faloidina/metabolismo
8.
Prog Mol Subcell Biol ; 57: 301-329, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30097780

RESUMO

Endocytosis is key in a number of cell events. In particular, its role during cell division has been a challenging question: while early studies examined whether endocytosis occurs during cell division, recent works show that, during division, cells do perform endocytosis actively. More importantly, during asymmetric cell division, endocytic pathways also control Notch signaling: endocytic vesicles regulate the presence, at the plasma membrane, of receptors and ligands at different levels between the two-daughter cells. Both early and late endocytic compartments have been shown to exert key regulatory controls by up-regulating or down-regulating Notch signaling in those cells. This biased Notch signaling enable finally cell fate assignation and specification which play a central role in development and physiology. In this chapter, we cover a number of significant works on endosomal trafficking evincing the importance of endocytosis in Notch-mediated cell fate specification during development.


Assuntos
Divisão Celular Assimétrica/genética , Endocitose/genética , Transporte Proteico/genética , Receptores Notch/genética , Animais , Membrana Celular/genética , Humanos , Ligantes , Transdução de Sinais/genética
9.
Phys Rev Lett ; 120(19): 198102, 2018 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-29799239

RESUMO

We present a theory of pattern formation in growing domains inspired by biological examples of tissue development. Gradients of signaling molecules regulate growth, while growth changes these graded chemical patterns by dilution and advection. We identify a critical point of this feedback dynamics, which is characterized by spatially homogeneous growth and proportional scaling of patterns with tissue length. We apply this theory to the biological model system of the developing wing of the fruit fly Drosophila melanogaster and quantitatively identify signatures of the critical point.


Assuntos
Padronização Corporal/fisiologia , Modelos Biológicos , Morfogênese/fisiologia , Animais , Drosophila melanogaster/crescimento & desenvolvimento , Modelos Animais , Transdução de Sinais
10.
J Am Chem Soc ; 139(30): 10172-10175, 2017 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-28741941

RESUMO

Quantum dots (QDs) are extremely bright, photostable, nanometer particles broadly used to investigate single molecule dynamics in vitro. However, the use of QDs in vivo to investigate single molecule dynamics is impaired by the absence of an efficient way to chemically deliver them into the cytosol of cells. Indeed, current methods (using cell-penetrating peptides for instance) provide very low yields: QDs stay at the plasma membrane or are trapped in endosomes. Here, we introduce a technology based on cell-penetrating poly(disulfide)s that solves this problem: we deliver about 70 QDs per cell, and 90% appear to freely diffuse in the cytosol. Furthermore, these QDs can be functionalized, carrying GFP or anti-GFP nanobodies for instance. Our technology thus paves the way toward single molecule imaging in cells and living animals, allowing to probe biophysical properties of the cytosol.


Assuntos
Peptídeos Penetradores de Células/química , Citosol/química , Dissulfetos/química , Sistemas de Liberação de Medicamentos , Pontos Quânticos/química , Animais , Linhagem Celular , Peptídeos Penetradores de Células/metabolismo , Citosol/metabolismo , Dissulfetos/metabolismo , Drosophila , Humanos , Estrutura Molecular , Pontos Quânticos/metabolismo
11.
Development ; 141(9): 1884-93, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24757005

RESUMO

During morphogenesis, organs grow to stereotyped sizes, but growth control mechanisms are poorly understood. Here, we measured the signaling dynamics of the morphogen Dpp, one of several Drosophila factors controlling morphogenetic growth, in the developing eye. In this tissue, the Dpp expression domain advances from the posterior to the anterior tissue edge. In front of this moving morphogen source, signaling inputs including Dpp activate the target gene hairy in a gradient that scales with tissue size. Proliferation, in turn, occurs in a mitotic wave in front of the source, whereas behind it, cells arrest and differentiate. We found that cells divide when their signaling levels have increased by around 60%. This simple mechanism quantitatively explains the proliferation and differentiation waves in wild type and mutants. Furthermore, this mechanism may be a common feature of different growth factors, because a Dpp-independent growth input also follows this growth rule.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Olho/metabolismo , Morfogênese , Animais , Proliferação de Células , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Olho/citologia , Discos Imaginais/citologia , Discos Imaginais/crescimento & desenvolvimento , Discos Imaginais/metabolismo , Modelos Biológicos , Mutação/genética , Transdução de Sinais , Fatores de Tempo
12.
Development ; 141(10): 2014-23, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24803650

RESUMO

Tissue homeostasis is maintained by adult stem cells, which self-renew and give rise to differentiating cells. The generation of daughter cells with different fates is mediated by signalling molecules coming from an external niche or being asymmetrically dispatched between the two daughters upon stem cell mitosis. In the adult Drosophila midgut, the intestinal stem cell (ISC) divides to generate a new ISC and an enteroblast (EB) differentiating daughter. Notch signalling activity restricted to the EB regulates intestinal cell fate decision. Here, we show that ISCs divide asymmetrically, and Sara endosomes in ISCs are specifically dispatched to the presumptive EB. During ISC mitosis, Notch and Delta traffic through Sara endosomes, thereby contributing to Notch signalling bias, as revealed in Sara mutants: Sara itself contributes to the control of the ISC asymmetric division. Our data uncover an intrinsic endosomal mechanism during ISC mitosis, which participates in the maintenance of the adult intestinal lineage.


Assuntos
Células-Tronco Adultas/citologia , Divisão Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Endossomos/metabolismo , Intestinos/citologia , Fator de Crescimento Transformador beta/metabolismo , Células-Tronco Adultas/fisiologia , Animais , Animais Geneticamente Modificados , Linhagem da Célula/genética , Polaridade Celular/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Mucosa Intestinal/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Mitose/fisiologia , Transporte Proteico/genética , Receptores Notch/metabolismo , Fator de Crescimento Transformador beta/genética
13.
J Am Chem Soc ; 137(2): 568-71, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25584496

RESUMO

In this report, "fluorescent flippers" are introduced to create planarizable push-pull probes with the mechanosensitivity and fluorescence lifetime needed for practical use in biology. Twisted push-pull scaffolds with large and bright dithienothiophenes and their S,S-dioxides as the first "fluorescent flippers" are shown to report on the lateral organization of lipid bilayers with quantum yields above 80% and lifetimes above 4 ns. Their planarization in liquid-ordered (Lo) and solid-ordered (So) membranes results in red shifts in excitation of up to +80 nm that can be transcribed into red shifts in emission of up to +140 nm by Förster resonance energy transfer (FRET). These unique properties are compatible with multidomain imaging in giant unilamellar vesicles (GUVs) and cells by confocal laser scanning or fluorescence lifetime imaging microscopy. Controls indicate that strong push-pull macrodipoles are important, operational probes do not relocate in response to lateral membrane reorganization, and two flippers are indeed needed to "really swim," i.e., achieve high mechanosensitivity.


Assuntos
Membrana Celular/química , Membrana Celular/metabolismo , Corantes Fluorescentes/química , Fenômenos Mecânicos , Fenômenos Biomecânicos , Desenho de Fármacos , Lipossomas Unilamelares/química
14.
Curr Opin Cell Biol ; 20(2): 137-43, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18329870

RESUMO

Two key processes are in the basis of morphogenesis: the spatial allocation of cell types in fields of naïve cells and the regulation of growth. Both are controlled by morphogens, which activate target genes in the growing tissue in a concentration-dependent manner. Thus the morphogen model is an intrinsically quantitative concept. However, quantitative studies were performed only in recent years on two morphogens: Bicoid and Decapentaplegic. This review covers quantitative aspects of the formation and precision of the Decapentaplegic morphogen gradient. The morphogen gradient concept is transitioning from a soft definition to a precise idea of what the gradient could really do.


Assuntos
Hormônios de Inseto/metabolismo , Morfogênese , Animais , Proteínas de Drosophila/metabolismo
15.
Curr Opin Cell Biol ; 20(4): 462-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18511252

RESUMO

Recent studies in vertebrate and invertebrate model organisms uncover the importance of endocytosis for biased signaling during asymmetric cell division. In stem cells, perturbing polarity and asymmetric division affect their selfrenewal causing exponential proliferation, thereby giving rise to cancer. An emerging pattern is that endocytosis controls asymmetric cell division, which underlies stem cell selfrenewal and defective selfrenewal is on the basis of tumorigenesis caused by cancer stem cells.


Assuntos
Endocitose/fisiologia , Neoplasias/patologia , Células-Tronco/citologia , Células-Tronco/patologia , Animais , Divisão Celular , Humanos , Neoplasias/genética
16.
Nat Rev Genet ; 10(8): 517-30, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19584811

RESUMO

The tissues of a developing embryo are simultaneously patterned, moved and differentiated according to an exchange of information between their constituent cells. We argue that these complex self-organizing phenomena can only be fully understood with quantitative mathematical frameworks that allow specific hypotheses to be formulated and tested. The quantitative and dynamic imaging of growing embryos at the molecular, cellular and tissue level is the key experimental advance required to achieve this interaction between theory and experiment. Here we describe how mathematical modelling has become an invaluable method to integrate quantitative biological information across temporal and spatial scales, serving to connect the activity of regulatory molecules with the morphological development of organisms.


Assuntos
Biologia do Desenvolvimento , Modelos Biológicos , Animais , Simulação por Computador , Humanos
17.
Commun Biol ; 7(1): 439, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600297

RESUMO

The phenomenal diversity of neuronal types in the central nervous system is achieved in part by the asymmetric division of neural precursors. In zebrafish neural precursors, asymmetric dispatch of Sara endosomes (with its Notch signaling cargo) functions as fate determinant which mediates asymmetric division. Here, we found two distinct pools of neural precursors based on Sara endosome inheritance and spindle-microtubule enrichment. Symmetric or asymmetric levels of spindle-microtubules drive differently Sara endosomes inheritance and predict neural precursor lineage. We uncover that CAMSAP2a/CAMSAP3a and KIF16Ba govern microtubule asymmetry and endosome motility, unveiling the heterogeneity of neural precursors. Using a plethora of physical and cell biological assays, we determined the physical parameters and molecular mechanisms behind microtubule asymmetries and biased endosome motility. Evolutionarily, the values of those parameters explain why all sensory organ precursor cells are asymmetric in flies while, in zebrafish spinal cord, two populations of neural precursors (symmetric vs asymmetric) are possible.


Assuntos
Proteínas de Drosophila , Peixe-Zebra , Animais , Endossomos , Microtúbulos , Medula Espinal
18.
Development ; 137(14): 2353-64, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20534670

RESUMO

In addition to apicobasal polarization, some epithelia also display polarity within the plane of the epithelium. To what extent polarized endocytosis plays a role in the establishment and maintenance of planar cell polarity (PCP) is at present unclear. Here, we investigated the role of Rabenosyn-5 (Rbsn-5), an evolutionarily conserved effector of the small GTPase Rab5, in the development of Drosophila wing epithelium. We found that Rbsn-5 regulates endocytosis at the apical side of the wing epithelium and, surprisingly, further uncovered a novel function of this protein in PCP. At early stages of pupal wing development, the PCP protein Fmi redistributes between the cortex and Rab5- and Rbsn-5-positive early endosomes. During planar polarization, Rbsn-5 is recruited at the apical cell boundaries and redistributes along the proximodistal axis in an Fmi-dependent manner. At pre-hair formation, Rbsn-5 accumulates at the bottom of emerging hairs. Loss of Rbsn-5 causes intracellular accumulation of Fmi and typical PCP alterations such as defects in cell packing, in the polarized distribution of PCP proteins, and in hair orientation and formation. Our results suggest that establishment of planar polarity requires the activity of Rbsn-5 in regulating both the endocytic trafficking of Fmi at the apical cell boundaries and hair morphology.


Assuntos
Polaridade Celular/fisiologia , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo , Animais , Polaridade Celular/genética , Drosophila/genética , Drosophila/metabolismo , Drosophila/fisiologia , Endocitose/genética , Endocitose/fisiologia , Morfogênese/genética , Morfogênese/fisiologia , Transporte Proteico/genética , Transporte Proteico/fisiologia , Asas de Animais/fisiologia
19.
Proc Natl Acad Sci U S A ; 107(52): 22558-63, 2010 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-21149700

RESUMO

Border cell migration is a stereotyped migration occurring during the development of the Drosophila egg chamber. During this process, a cluster composed of six to eight follicle cells migrates between nurse cells toward the oocyte. Receptor tyrosine kinases (RTKs) are enriched at the leading edge of the follicle cells and establish the directionality of their migration. Endocytosis has been shown to play a role in the maintenance of this polarization; however, the mechanisms involved are largely unknown. In this study, we show that border cell migration requires the function of the small GTPases Rab5 and Rab11 that regulate trafficking through the early and the recycling endosome, respectively. Expression of a dominant negative form of rab11 induces a loss of the polarization of RTK activity, which correlates with a severe migration phenotype. In addition, we demonstrate that the exocyst component Sec15 is distributed in structures that are polarized during the migration process in a Rab11-dependent manner and that the down-regulation of different subunits of the exocyst also affects migration. Together, our data demonstrate a fundamental role for a plasma membrane-endosome trafficking cycle in the maintenance of active RTK at the leading edge of border cells during their migration.


Assuntos
Movimento Celular/fisiologia , Endocitose/fisiologia , Oócitos/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Polaridade Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Endossomos/metabolismo , Receptores ErbB/metabolismo , Feminino , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microscopia Confocal , Oócitos/citologia , Interferência de RNA , Receptores de Peptídeos de Invertebrados/metabolismo , Fatores de Tempo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab4 de Ligação ao GTP/genética , Proteínas rab4 de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7
20.
Trends Cell Biol ; 33(2): 92-94, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36241583

RESUMO

The transforming growth factor-ß (TGF-ß)-type morphogens are conserved throughout the animal kingdom. TGF-ß-type molecules form spatial concentration gradients whose length scales with the size of growing, developing organs. Scaling of these morphogens can also be mediated by death, adjusting the size of the tissue to the range of the gradient. Death-mediated scaling might provide a molecular toolbox exploited by cancer cells.


Assuntos
Fator de Crescimento Transformador beta , Animais , Morfogênese
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA