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1.
Int J Mol Sci ; 25(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339183

RESUMO

The main characteristic of polycystic kidney disease is the development of multiple fluid-filled renal cysts. The discovery of mislocalized sodium-potassium pump (Na,K-ATPase) in the apical membrane of cyst-lining epithelia alluded to reversal of polarity as a possible explanation for the fluid secretion. The topic of apical Na,K-ATPase in cysts remains controversial. We investigated the localization of the Na,K-ATPase and assessed the apical-basolateral polarization of cyst-lining epithelia by means of immunohistochemistry in kidney tissue from six polycystic kidney disease patients undergoing nephrectomy. The Na,K-ATPase α1 subunit was conventionally situated in the basolateral membrane of all immunoreactive cysts. Proteins of the Crumbs and partitioning defective (Par) complexes were localized to the apical membrane domain in cyst epithelial cells. The apical targeting protein Syntaxin-3 also immunolocalized to the apical domain of cyst-lining epithelial cells. Proteins of the basolateral Scribble complex immunolocalized to the basolateral domain of cysts. Thus, no deviations from the typical epithelial distribution of basic cell polarity proteins were observed in the cysts from the six patients. Furthermore, we confirmed that cysts can originate from virtually any tubular segment with preserved polarity. In conclusion, we find no evidence of a reversal in apical-basolateral polarity in cyst-lining epithelia in polycystic kidney disease.


Assuntos
Cistos , Doenças Renais Policísticas , Humanos , ATPase Trocadora de Sódio-Potássio/metabolismo , Polaridade Celular , Doenças Renais Policísticas/metabolismo , Epitélio/metabolismo , Membrana Celular/metabolismo , Proteínas Qa-SNARE/metabolismo , Cistos/metabolismo , Rim/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(21): 11531-11540, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32414916

RESUMO

A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scribble (Scrib) module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Discs-large (Dlg), and Lethal giant larvae (Lgl) using the Drosophila follicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein-protein interactions as essential for polarization. Cortical recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize atypical protein kinase C (aPKC), but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg, and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.


Assuntos
Polaridade Celular/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila , Células Epiteliais , Proteínas de Membrana/fisiologia , Animais , Drosophila/citologia , Drosophila/fisiologia , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Epitélio/fisiologia , Feminino , Folículo Ovariano/citologia , Folículo Ovariano/fisiologia , Proteína Quinase C , Proteínas Supressoras de Tumor
3.
Development ; 146(8)2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918053

RESUMO

Local signals and structural support from the surrounding cellular microenvironment play key roles in directing development in both embryonic organs and adult tissues. In Drosophila, male germ cells are intimately associated and co-differentiate with supporting somatic cells. Here, we show that the function of the Baz/aPKC/Par6 apical polarity complex in somatic cyst cells is required stage specifically for survival of the germ cells they enclose. Although spermatogonia enclosed by cyst cells in which the function of the Par complex had been knocked down survived and proliferated, newly formed spermatocytes enclosed by cyst cells lacking Par complex proteins died soon after onset of meiotic prophase. Loss of Par complex function resulted in stage-specific overactivation of the Jun-kinase (JNK) pathway in cyst cells. Knocking down expression of JNK pathway components or the GTPase Rab35 in cyst cells lacking Par complex function rescued the survival of neighboring spermatocytes, suggesting that action of the apical polarity complex ensures germ cell survival by preventing JNK pathway activation, and that the mechanism by which cyst cells lacking Par complex function kill neighboring spermatocytes requires intracellular trafficking in somatic cyst cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/citologia , Drosophila/metabolismo , Células Germinativas/citologia , Células Germinativas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Quinase C/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Polaridade Celular/genética , Polaridade Celular/fisiologia , Proteínas de Drosophila/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mitose/genética , Mitose/fisiologia , Proteína Quinase C/genética
4.
Development ; 146(15)2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405903

RESUMO

Cdc42 regulates epithelial morphogenesis together with the Par complex (Baz/Par3-Par6-aPKC), Crumbs (Crb/CRB3) and Stardust (Sdt/PALS1). However, how these proteins work together and interact during epithelial morphogenesis is not well understood. To address this issue, we used the genetically amenable Drosophila pupal photoreceptor and follicular epithelium. We show that during epithelial morphogenesis active Cdc42 accumulates at the developing apical membrane and cell-cell contacts, independently of the Par complex and Crb. However, membrane localization of Baz, Par6-aPKC and Crb all depend on Cdc42. We find that although binding of Cdc42 to Par6 is not essential for the recruitment of Par6 and aPKC to the membrane, it is required for their apical localization and accumulation, which we find also depends on Par6 retention by Crb. In the pupal photoreceptor, membrane recruitment of Par6-aPKC also depends on Baz. Our work shows that Cdc42 is required for this recruitment and suggests that this factor promotes the handover of Par6-aPKC from Baz onto Crb. Altogether, we propose that Cdc42 drives morphogenesis by conferring apical identity, Par-complex assembly and apical accumulation of Crb.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Membrana/metabolismo , Células Fotorreceptoras/citologia , Proteína Quinase C/metabolismo , Animais , Polaridade Celular/fisiologia , Drosophila melanogaster/metabolismo , Epitélio/crescimento & desenvolvimento , Morfogênese/fisiologia , Ligação Proteica/fisiologia
5.
Int J Mol Sci ; 23(9)2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35563080

RESUMO

Cellular trafficking through the endosomal-lysosomal system is essential for the transport of cargo proteins, receptors and lipids from the plasma membrane inside the cells and across membranous organelles. By acting as sorting stations, vesicle compartments direct the fate of their content for degradation, recycling to the membrane or transport to the trans-Golgi network. To effectively communicate with their neighbors, cells need to regulate their compartmentation and guide their signaling machineries to cortical membranes underlying these contact sites. Endosomal trafficking is indispensable for the polarized distribution of fate determinants, adaptors and junctional proteins. Conversely, endocytic machineries cooperate with polarity and scaffolding components to internalize receptors and target them to discrete membrane domains. Depending on the cell and tissue context, receptor endocytosis can terminate signaling responses but can also activate them within endosomes that act as signaling platforms. Therefore, cell homeostasis and responses to environmental cues rely on the dynamic cooperation of endosomal-lysosomal machineries with polarity and signaling cues. This review aims to address advances and emerging concepts on the cooperative regulation of endocytosis, polarity and signaling, primarily in Drosophila melanogaster and discuss some of the open questions across the different cell and tissue types that have not yet been fully explored.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Endocitose , Endossomos/metabolismo , Transporte Proteico , Transdução de Sinais
6.
J Cell Sci ; 132(10)2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113848

RESUMO

Cdc42 - a member of the small Rho GTPase family - regulates cell polarity across organisms from yeast to humans. It is an essential regulator of polarized morphogenesis in epithelial cells, through coordination of apical membrane morphogenesis, lumen formation and junction maturation. In parallel, work in yeast and Caenorhabditiselegans has provided important clues as to how this molecular switch can generate and regulate polarity through localized activation or inhibition, and cytoskeleton regulation. Recent studies have revealed how important and complex these regulations can be during epithelial morphogenesis. This complexity is mirrored by the fact that Cdc42 can exert its function through many effector proteins. In epithelial cells, these include atypical PKC (aPKC, also known as PKC-3), the P21-activated kinase (PAK) family, myotonic dystrophy-related Cdc42 binding kinase beta (MRCKß, also known as CDC42BPB) and neural Wiskott-Aldrich syndrome protein (N-WASp, also known as WASL). Here, we review how the spatial regulation of Cdc42 promotes polarity and polarized morphogenesis of the plasma membrane, with a focus on the epithelial cell type.


Assuntos
Células Epiteliais/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Células Epiteliais/citologia , Humanos , Morfogênese
7.
Int J Mol Sci ; 22(22)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34830224

RESUMO

Cell polarity is essential for many functions of cells and tissues including the initial establishment and subsequent maintenance of epithelial tissues, asymmetric cell division, and morphogenetic movements. Cell polarity along the apical-basal axis is controlled by three protein complexes that interact with and co-regulate each other: The Par-, Crumbs-, and Scrib-complexes. The localization and activity of the components of these complexes is predominantly controlled by protein-protein interactions and protein phosphorylation status. Increasing evidence accumulates that, besides the regulation at the protein level, the precise expression control of polarity determinants contributes substantially to cell polarity regulation. Here we review how gene expression regulation influences processes that depend on the induction, maintenance, or abolishment of cell polarity with a special focus on epithelial to mesenchymal transition and asymmetric stem cell division. We conclude that gene expression control is an important and often neglected mechanism in the control of cell polarity.


Assuntos
Divisão Celular Assimétrica/genética , Polaridade Celular/genética , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica , Transcrição Gênica/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas do Olho/metabolismo , Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo
8.
Biochim Biophys Acta Mol Cell Res ; 1865(9): 1201-1210, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29842893

RESUMO

Pleural fibrosis is barely reversible and the underlying mechanisms are poorly understood. Pleural mesothelial cells (PMCs) which have apical-basal polarity play a key role in pleural fibrosis. Loss of cell polarity is involved in the development of fibrotic diseases. Partition defective protein (PAR) complex is a key regulator of cell polarity. However, changes of PMC polarity and PAR complex in pleural fibrosis are still unknown. In this study, we observed that PMC polarity was lost in fibrotic pleura. Next we found increased Lethal (2) giant larvae (Lgl) bound with aPKC and PAR-6B competing against PAR-3A in PAR complex, which led to cell polarity loss. Then we demonstrated that Lgl1 siRNA prevented cell polarity loss in PMCs, and Lgl1 conditional knockout (ER-Cre+/-Lgl1flox/flox) attenuated pleural fibrosis in a mouse model. Our data indicated that Lgl1 regulates cell polarity of PMCs, inhibition of Lgl1 and maintenance of cell polarity in PMCs could be a potential therapeutic treatment approach for pleural fibrosis.


Assuntos
Células Epiteliais/citologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Pleura/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Polaridade Celular , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Fibrose , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Pleura/metabolismo , Proteína Quinase C/metabolismo , Ratos
9.
J Cell Sci ; 130(7): 1201-1207, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28365593

RESUMO

Cells exhibit morphological and molecular asymmetries that are broadly categorized as cell polarity. The cell polarity established in early embryos prefigures the macroscopic anatomical asymmetries characteristic of adult animals. For example, eggs and early embryos have polarized distributions of RNAs and proteins that generate global anterior/posterior and dorsal/ventral axes. The molecular programs that polarize embryos are subsequently reused in multiple contexts. Epithelial cells require apical/basal polarity to establish their barrier function. Migrating cells polarize in the direction of movement, creating distinct leading and trailing structures. Asymmetrically dividing stem cells partition different molecules between themselves and their daughter cells. Cell polarity can develop de novo, be maintained through rounds of cell division and be dynamically remodeled. In this Cell Science at a Glance review and poster, we describe molecular asymmetries that underlie cell polarity in several cellular contexts. We highlight multiple developmental systems that first establish cell/developmental polarity, and then maintain it. Our poster showcases repeated use of the Par, Scribble and Crumbs polarity complexes, which drive the development of cell polarity in many cell types and organisms. We then briefly discuss the diverse and dynamic changes in cell polarity that occur during cell migration, asymmetric cell division and in planar polarized tissues.


Assuntos
Polaridade Celular , Animais , Divisão Celular Assimétrica , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Movimento Celular , Humanos , Complexos Multiproteicos/metabolismo , Transdução de Sinais
10.
Mol Carcinog ; 57(11): 1640-1650, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30084175

RESUMO

Altered cell polarity and migration are hallmarks of cancer and metastases. Here we show that inactivation of the retinoblastoma gene (Rb) tumor suppressor causes defects in tissue closure that reflect the inability of Rb null epithelial cells to efficiently migrate and polarize. These defects occur independently of pRB's anti-proliferative role and instead correlate with upregulation of RhoA signaling and mislocalization of apical-basal polarity proteins. Notably, concomitant inactivation of tp53 specifically overrides the motility defect, and not the aberrant polarity, thereby uncovering previously unappreciated mechanisms by which Rb and tp53 mutations cooperate to promote cancer development and metastases.


Assuntos
Movimento Celular/genética , Polaridade Celular/genética , Células Epiteliais/metabolismo , Proteína do Retinoblastoma/genética , Proteínas Supressoras de Tumor/genética , Proteínas de Fase Aguda/metabolismo , Animais , Inativação Gênica , Humanos , Camundongos , Mutação , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo
11.
Int J Mol Sci ; 19(7)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011834

RESUMO

Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of membrane components; and (ii) TJ regulate the selective paracellular permeability. Disruption of TJ is regarded as one of the earliest hallmarks of epithelial injury, leading to the loss of cell polarity and tissue disorganization. Many factors have been identified as modulators of TJ assembly/disassembly. More specifically, in addition to its role as an energy sensor, adenosine monophosphate-activated protein kinase (AMPK) participates in TJ regulation. AMPK is a ubiquitous serine/threonine kinase composed of a catalytic α-subunit complexed with regulatory ß-and γ-subunits. AMPK activation promotes the early stages of epithelial TJ assembly. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the TJ-associated protein zonula occludens (ZO)-1, thereby facilitating ZO-1 distribution to the plasma membrane. In the present review, we detail the signaling pathways up-and down-stream of AMPK activation at the time of Ca2+-induced TJ assembly.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Membrana Celular/metabolismo , Células Epiteliais/metabolismo , Junções Íntimas/metabolismo , Animais , Polaridade Celular , Humanos , Ligação Proteica , Subunidades Proteicas/metabolismo , Proteínas de Junções Íntimas/metabolismo
12.
J Cell Biochem ; 117(10): 2215-23, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27362918

RESUMO

Breast cancer, one of the leading causes of cancer related death in women worldwide, is a heterogeneous disease with diverse subtypes that have different properties and prognoses. The developing mammary gland is a highly proliferative and invasive tissue, and some of the developmental programs may be aberrantly activated to promote breast cancer progression. In the breast, luminal epithelial cells exhibit apical-basal polarity, and the failure to maintain this organizational structure, due to disruption of polarity complexes, is implicated in promoting hyperplasia and tumors. Therefore, understanding the mechanisms underlying loss of polarity will contribute to our knowledge of the early stages leading to the pathogenesis of the disease. In this review, we will discuss recent findings that support the idea that loss of apical-basal cell polarity is a crucial step in the acquisition of the malignant phenotype. Oncogene induced loss of tissue organization shares a conserved cellular mechanism with developmental process, we will further describe the role of the individual polarity complexes, the Par, Crumbs, and Scribble, to couple cell division orientation and cell growth. We will examine symmetric or asymmetric cell divisions in mammary stem cell and their contribution to the development of breast cancer subtypes and cancer stem cells. Finally, we will highlight some of the recent advances in our understanding of the molecular mechanisms by which changes in epithelial polarity programs promote invasion and metastasis through single cell and collective cell modes. J. Cell. Biochem. 117: 2215-2223, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Polaridade Celular , Células Epiteliais/patologia , Animais , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Células Epiteliais/metabolismo , Feminino , Humanos
13.
Am J Physiol Renal Physiol ; 311(1): F112-9, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27122542

RESUMO

Polarity signaling through the atypical PKC (aPKC)-Par polarity complex is essential for the development and maintenance of the podocyte architecture and the function of the glomerular filtration barrier of the kidney. To study the contribution of Par3A in this complex, we generated a novel Pard3 podocyte-specific knockout mouse model by targeting exon 6 of the Pard3 gene. Genetic deletion of Pard3a did not impair renal function, neither at birth nor later in life. Even challenging the animals did not result in glomerular disease. Despite its well-established role in aPKC-mediated signaling, Par3A appears to be dispensable for the function of the glomerular filtration barrier. Moreover, its homolog Pard3b, and not Pard3a, is the dominant Par3 gene expressed in podocytes and found at the basis of the slit diaphragm, where it partially colocalizes with podocin. In conclusion, Par3A function is either dispensable for slit diaphragm integrity, or compensatory mechanisms and a high redundancy of the different polarity proteins, including Par3B, Lgl, or PALS1, maintain the function of the glomerular filtration barrier, even in the absence of Par3A.


Assuntos
Moléculas de Adesão Celular/metabolismo , Barreira de Filtração Glomerular/fisiologia , Rim/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Moléculas de Adesão Celular/genética , Proteínas de Ciclo Celular , Células Cultivadas , Feminino , Rim/patologia , Lipopolissacarídeos/toxicidade , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Núcleosídeo-Fosfato Quinase/genética , Núcleosídeo-Fosfato Quinase/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia , Cultura Primária de Células , Soroalbumina Bovina/toxicidade
14.
J Cell Sci ; 127(Pt 20): 4381-95, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25179599

RESUMO

Inflammatory cells acquire a polarized phenotype to migrate towards sites of infection or injury. A conserved polarity complex comprising PAR-3, PAR-6 and atypical protein kinase C (aPKC) relays extracellular polarizing cues to control cytoskeletal and signaling networks affecting morphological and functional polarization. However, there is no evidence that myeloid cells use PAR signaling to migrate vectorially in three-dimensional (3D) environments in vivo. Using genetically encoded bioprobes and high-resolution live imaging, we reveal the existence of F-actin oscillations in the trailing edge and constant repositioning of the microtubule organizing center (MTOC) to direct leukocyte migration in wounded medaka fish larvae (Oryzias latipes). Genetic manipulation in live myeloid cells demonstrates that the catalytic activity of aPKC and the regulated interaction with PAR-3 and PAR-6 are required for consistent F-actin oscillations, MTOC perinuclear mobility, aPKC repositioning and wound-directed migration upstream of Rho kinase (also known as ROCK or ROK) activation. We propose that the PAR complex coordinately controls cytoskeletal changes affecting both the generation of traction force and the directionality of leukocyte migration to sites of injury.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/metabolismo , Movimento Celular , Leucócitos/fisiologia , Centro Organizador dos Microtúbulos/fisiologia , Proteína Quinase C/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Animais Geneticamente Modificados , Proteínas de Transporte/genética , Polaridade Celular/genética , Células Cultivadas , Complexos Multiproteicos/genética , Mutação/genética , Oryzias , Proteína Quinase C/genética , Transporte Proteico , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Quinases Associadas a rho/metabolismo
15.
Dev Biol ; 390(1): 41-50, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24607370

RESUMO

Branching morphogenesis, the process by which cells or tissues generate tree-like networks that function to increase surface area or in contacting multiple targets, is a common developmental motif in multicellular organisms. We use Drosophila tracheal terminal cells, a component of the insect respiratory system, to investigate branching morphogenesis that occurs at the single cell level. Here, we show that the exocyst, a conserved protein complex that facilitates docking and tethering of vesicles at the plasma membrane, is required for terminal cell branch outgrowth. We find that exocyst-deficient terminal cells have highly truncated branches and show an accumulation of vesicles within their cytoplasm and are also defective in subcellular lumen formation. We also show that vesicle trafficking pathways mediated by the Rab GTPases Rab10 and Rab11 are redundantly required for branch outgrowth. In terminal cells, the PAR-polarity complex is required for branching, and we find that the PAR complex is required for proper membrane localization of the exocyst, thus identifying a molecular link between the branching and outgrowth programs. Together, our results suggest a model where exocyst mediated vesicle trafficking facilitates branch outgrowth, while de novo branching requires cooperation between the PAR and exocyst complexes.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Traqueia/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Animais Geneticamente Modificados , Transporte Biológico/genética , Proliferação de Células , Vesículas Citoplasmáticas/metabolismo , Vesículas Citoplasmáticas/ultraestrutura , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Endocitose/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Morfogênese/genética , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Interferência de RNA , Traqueia/citologia , Traqueia/crescimento & desenvolvimento , Proteínas de Transporte Vesicular/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
16.
Placenta ; 141: 26-34, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-36443107

RESUMO

Maintenance of cell polarity and the structure of the apical surface of epithelial cells is a tightly regulated process necessary for tissue homeostasis. The syncytiotrophoblast of the human placenta is an entirely unique epithelial layer. It is a single giant multinucleate syncytial layer that comprises the maternal-facing surface of the human placenta. Like other epithelia, the syncytiotrophoblast is highly polarized with the apical surface dominated by microvillar membrane protrusions. Syncytiotrophoblast dysfunction is a key feature of pregnancy complications like preeclampsia. Preeclampsia is commonly associated with a heightened maternal immune response and pro-inflammatory environment. Importantly, reports have observed disruption of syncytiotrophoblast apical microvilli in placentas from preeclamptic pregnancies, indicating a loss of apical polarity, but little is known about how the syncytiotrophoblast regulates polarity. Here, we review the evolutionarily conserved mechanisms that regulate apical-basal polarization in epithelial cells, and the emerging evidence that PAR polarity complex components are critical regulators of syncytiotrophoblast homeostasis and apical membrane structure. Pro-inflammatory cytokines have been shown to disrupt the expression of polarity regulating proteins. We also discuss initial data showing that syncytiotrophoblast apical polarity can be disrupted by the addition of the pro-inflammatory cytokine tumor necrosis factor-α, revealing that physiologically relevant signals can modulate syncytiotrophoblast polarization. Since disrupted polarity is a feature of preeclampsia, further elucidation of the syncytiotrophoblast-specific polarity signaling network and testing whether the disruption of polarity-factor signaling networks may contribute to the development of preeclampsia is warranted.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Feminino , Humanos , Gravidez , Polaridade Celular/fisiologia , Homeostase , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Trofoblastos/metabolismo
17.
Mol Biotechnol ; 64(12): 1319-1327, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35610404

RESUMO

The tripartite partition defect (PAR) polarity complex, which includes the proteins PAR3, atypical protein kinase C (aPKC), and PAR6, is a major regulator of cellular polarity. It is highly conserved and expressed in various tissues. Its largest component, PAR3, controls protein-protein interactions of the PAR complex with a variety of interaction partners, and PAR3 self-association is critical for the formation of filament-like structures. However, little is known about the structure of the PAR complex. Here, we purified non-filamentous PAR3 and the aPKC-PAR6 complex and characterized them by single-particle electron microscopy (EM). We expressed and purified an oligomerization-deficient form of PAR3, PAR3V13D,D70K, and the active aPKC-PAR6 dimer. For PAR3, engineering at two positions is sufficient to form stable single particles with a maximum dimension of 20 nm. aPKC-PAR6 forms a complex with a maximum dimension of 13.5 nm that contains single copies of aPKC. Thus, the data present a basis for further high-resolution studies of PAR proteins and PAR complex formation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Quinase C , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Polaridade Celular , Humanos , Proteína Quinase C/genética , Proteína Quinase C/metabolismo
18.
Dev Cell ; 57(21): 2483-2496.e4, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36347240

RESUMO

Collective cell movements drive normal development and metastasis. Drosophila border cells move as a cluster of 6-10 cells, where the role of the Rac GTPase in migration was first established. In border cells, as in most migratory cells, Rac stimulates leading-edge protrusion. Upstream Rac regulators in leaders have been identified; however, the regulation and function of Rac in follower border cells is unknown. Here, we show that all border cells require Rac, which promotes follower-cell motility and is important for cluster compactness and movement. We identify a Rac guanine nucleotide exchange factor, Cdep, which also regulates follower-cell movement and cluster cohesion. Scribble, Discs large, and Lethal giant larvae localize Cdep basolaterally and share phenotypes with Cdep. Relocalization of Cdep::GFP partially rescues Scribble knockdown, suggesting that Cdep is a major downstream effector of basolateral proteins. Thus, a Scrib/Cdep/Rac pathway promotes cell crawling and coordinated, collective migration in vivo.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Movimento Celular/fisiologia , Drosophila/metabolismo , Piperazinas/metabolismo , Oogênese , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Polaridade Celular/fisiologia
19.
FEBS J ; 288(24): 7073-7095, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33448150

RESUMO

Cell polarity is a fundamental property of most animal cells and is critical during development and for most cell and tissue functions. Epithelial cells are organized into apical and basolateral compartments, and this intrinsic cellular asymmetry is essential for all functions that are carried out by epithelial tissue. The establishment of a polarized epithelial phenotype is orchestrated by major rearrangements of the cell cytoskeleton, polarized membrane trafficking, the formation and maturation of epithelial cell junctions, cell signaling pathways, and the generation of cortical phospholipid asymmetry. These processes need to be coordinated precisely in time and space and integrated with physical and chemical signals from the environment, failure of which leads to severe developmental disorders and various human diseases. At the heart of this regulatory network are the evolutionarily conserved polarity modules Par, Crumbs, and Scribble, whose components engage in complex cooperative and antagonistic interactions to compartmentalize and functionalize the epithelial cell cortex and to control the spatiotemporal activity of downstream polarity effectors. In this review, we will discuss recent insights into the organization and regulation of the mammalian Par and Crumbs modules and outline a hypothetical framework of how these proteins orchestrate epithelial polarity development, HIPPO signaling, and actomyosin activity at the apical-lateral border.


Assuntos
Células Epiteliais/metabolismo , Animais , Polaridade Celular , Células Epiteliais/citologia , Humanos
20.
Curr Biol ; 31(17): 3768-3783.e3, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34270949

RESUMO

Neurons are highly polarized cells with morphologically and functionally distinct dendritic and axonal processes. The molecular mechanisms that establish axon-dendrite polarity in vivo are poorly understood. Here, we describe the initial polarization of posterior deirid (PDE), a ciliated mechanosensory neuron, during development in vivo through 4D live imaging with endogenously tagged proteins. PDE inherits and maintains apicobasal polarity from its epithelial precursor. Its apical domain is directly transformed into the ciliated dendritic tip through apical constriction, which is followed by axonal outgrowth from the opposite basal side of the cell. The apical Par complex and junctional proteins persistently localize at the developing dendritic domain throughout this transition. Consistent with their instructive role in axon-dendrite polarization, conditional depletion of the Par complex and junctional proteins results in robust defects in dendrite and axon formation. During apical constriction, a microtubule-organizing center (MTOC) containing the microtubule nucleator γ-tubulin ring complex (γ-TuRC) forms along the apical junction between PDE and its sister cell in a manner dependent on the Par complex and junctional proteins. This junctional MTOC patterns neuronal microtubule polarity and facilitate the dynein-dependent recruitment of the basal body for ciliogenesis. When non-ciliated neurons are genetically manipulated to obtain ciliated neuronal fate, inherited apicobasal polarity is required for generating ciliated dendritic tips. We propose that inherited apicobasal polarity, together with apical cell-cell interactions drive the morphological and cytoskeletal polarity in early neuronal differentiation.


Assuntos
Axônios , Centro Organizador dos Microtúbulos , Polaridade Celular/fisiologia , Dendritos/metabolismo , Centro Organizador dos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Células Receptoras Sensoriais
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