scholarly journals The Ski2-family helicase Obelus regulates Crumbs alternative splicing and cell polarity

2015 ◽  
Vol 211 (5) ◽  
pp. 1011-1024 ◽  
Author(s):  
Athea Vichas ◽  
Matthew T. Laurie ◽  
Jennifer A. Zallen
Keyword(s):  
Alternative Splicing ◽  
Cell Polarity ◽  
Adherens Junction ◽  
Early Embryo ◽  
Epithelial Polarity ◽  
Protein Activity ◽  
Splicing Regulators ◽  
Apical Domain ◽  
Apical Polarity ◽  
Epidermal Growth

Alternative splicing can have profound consequences for protein activity, but the functions of most alternative splicing regulators are not known. We show that Obelus, a conserved Ski2-family helicase, is required for cell polarity and adherens junction organization in the Drosophila melanogaster embryo. In obelus mutants, epithelial cells display an expanded apical domain, aggregation of adherens junctions at the cell membrane, and microtubule-dependent defects in centrosome positioning. Through whole-genome transcriptome analysis, we found that Obelus is required for the alternative splicing of a small number of transcripts in the early embryo, including the pre-mRNA that encodes the apical polarity protein Crumbs. In obelus mutants, inclusion of an alternative exon results in increased expression of a Crumbs isoform that contains an additional epidermal growth factor–like repeat in the extracellular domain. Overexpression of this alternative Crumbs isoform recapitulates the junctional aggregation and centrosome positioning defects of obelus mutants. These results indicate that regulation of Crumbs alternative splicing by the Obelus helicase modulates epithelial polarity during development.

scholarly journals Interplay of MPP5a with Rab11 synergistically builds epithelial apical polarity and zonula adherens

Development ◽  
2020 ◽  
Vol 147 (22) ◽  
pp. dev184457
Author(s):  
Yumei Hao ◽  
Yao Zhou ◽  
Yinhui Yu ◽  
Mingjie Zheng ◽  
Kechao Weng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Driving Force ◽  
Adherens Junction ◽  
Small Gtpase ◽  
Epithelial Polarity ◽  
Apical Domain ◽  
Neuroepithelial Cells ◽  
Apical Polarity ◽  
Crumbs Complex ◽  
Remodeling Pattern

ABSTRACTAdherens junction remodeling regulated by apical polarity proteins constitutes a major driving force for tissue morphogenesis, although the precise mechanism remains inconclusive. Here, we report that, in zebrafish, the Crumbs complex component MPP5a interacts with small GTPase Rab11 in Golgi to transport cadherin and Crumbs components synergistically to the apical domain, thus establishing apical epithelial polarity and adherens junctions. In contrast, Par complex recruited by MPP5a is incapable of interacting with Rab11 but might assemble cytoskeleton to facilitate cadherin exocytosis. In accordance, dysfunction of MPP5a induces an invasive migration of epithelial cells. This adherens junction remodeling pattern is frequently observed in zebrafish lens epithelial cells and neuroepithelial cells. The data identify an unrecognized MPP5a-Rab11 complex and describe its essential role in guiding apical polarization and zonula adherens formation in epithelial cells.

scholarly journals Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila

2004 ◽  
Vol 167 (1) ◽  
pp. 135-147 ◽  
Author(s):  
Tony J.C. Harris ◽  
Mark Peifer
Keyword(s):  
Epithelial Cell ◽  
Cell Polarity ◽  
Cell Morphology ◽  
Adherens Junction ◽  
Epithelial Polarity ◽  
Cell Dissociation ◽  
Epithelial Cell Polarity ◽  
Apical Domain ◽  
Discs Large ◽  
Polarity Establishment

Adherens junctions (AJs) are thought to be key landmarks for establishing epithelial cell polarity, but the origin of epithelial polarity in Drosophila remains unclear. Thus, we examined epithelial polarity establishment during early Drosophila development. We found apical accumulation of both Drosophila E-Cadherin (DE-Cad) and the apical cue Bazooka (Baz) as cells first form. Mutant analyses revealed that apical Baz accumulations can be established in the absence of AJs, whereas assembly of apical DE-Cad complexes requires Baz. Thus, Baz acts upstream of AJs during epithelial polarity establishment. During gastrulation the absence of AJs results in widespread cell dissociation and depolarization. Some epithelial structures are retained, however. These structures maintain apical Baz, accumulate apical Crumbs, and organize polarized cytoskeletons, but display abnormal cell morphology and fail to segregate the basolateral cue Discs large from the apical domain. Thus, although epithelial polarity develops in the absence of AJs, AJs play specific roles in maintaining epithelial architecture and segregating basolateral cues.

scholarly journals The positioning and segregation of apical cues during epithelial polarity establishment in Drosophila

2005 ◽  
Vol 170 (5) ◽  
pp. 813-823 ◽  
Author(s):  
Tony J.C. Harris ◽  
Mark Peifer
Keyword(s):  
Protein Kinase C ◽  
Cell Polarity ◽  
Structure And Function ◽  
Epithelial Polarity ◽  
Kinase C ◽  
Binding Partners ◽  
Apical Domain ◽  
Epithelial Structure ◽  
And Function ◽  
Key Steps

Cell polarity is critical for epithelial structure and function. Adherens junctions (AJs) often direct this polarity, but we previously found that Bazooka (Baz) acts upstream of AJs as epithelial polarity is first established in Drosophila. This prompted us to ask how Baz is positioned and how downstream polarity is elaborated. Surprisingly, we found that Baz localizes to an apical domain below its typical binding partners atypical protein kinase C (aPKC) and partitioning defective (PAR)-6 as the Drosophila epithelium first forms. In fact, Baz positioning is independent of aPKC and PAR-6 relying instead on cytoskeletal cues, including an apical scaffold and dynein-mediated basal-to-apical transport. AJ assembly is closely coupled to Baz positioning, whereas aPKC and PAR-6 are positioned separately. This forms a stratified apical domain with Baz and AJs localizing basal to aPKC and PAR-6, and we identify specific mechanisms that keep these proteins apart. These results reveal key steps in the assembly of the apical domain in Drosophila.

scholarly journals Splicing-associated chromatin signatures: a combinatorial and position-dependent role for histone marks in splicing definition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
E. Agirre ◽  
A. J. Oldfield ◽  
N. Bellora ◽  
A. Segelle ◽  
R. F. Luco
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Chromatin Modifications ◽  
Histone Marks ◽  
Splicing Regulators ◽  
Machine Learning Approach ◽  
Alternatively Spliced ◽  
Rna Motif ◽  
Regulation Changes

AbstractAlternative splicing relies on the combinatorial recruitment of splicing regulators to specific RNA binding sites. Chromatin has been shown to impact this recruitment. However, a limited number of histone marks have been studied at a global level. In this work, a machine learning approach, applied to extensive epigenomics datasets in human H1 embryonic stem cells and IMR90 foetal fibroblasts, has identified eleven chromatin modifications that differentially mark alternatively spliced exons depending on the level of exon inclusion. These marks act in a combinatorial and position-dependent way, creating characteristic splicing-associated chromatin signatures (SACS). In support of a functional role for SACS in coordinating splicing regulation, changes in the alternative splicing of SACS-marked exons between ten different cell lines correlate with changes in SACS enrichment levels and recruitment of the splicing regulators predicted by RNA motif search analysis. We propose the dynamic nature of chromatin modifications as a mechanism to rapidly fine-tune alternative splicing when necessary.

scholarly journals CD13 orients the apical-basal polarity axis necessary for lumen formation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Li-Ting Wang ◽  
Abira Rajah ◽  
Claire M. Brown ◽  
Luke McCaffrey
Keyword(s):  
Epithelial Cells ◽  
Apical Membrane ◽  
Initiation Site ◽  
Outer Cell ◽  
Cell Periphery ◽  
Complex Structures ◽  
Peptidase Activity ◽  
Epithelial Polarity ◽  
Lumen Formation ◽  
Apical Domain

AbstractPolarized epithelial cells can organize into complex structures with a characteristic central lumen. Lumen formation requires that cells coordinately orient their polarity axis so that the basolateral domain is on the outside and apical domain inside epithelial structures. Here we show that the transmembrane aminopeptidase, CD13, is a key determinant of epithelial polarity orientation. CD13 localizes to the apical membrane and associates with an apical complex with Par6. CD13-deficient cells display inverted polarity in which apical proteins are retained on the outer cell periphery and fail to accumulate at an intercellular apical initiation site. Here we show that CD13 is required to couple apical protein cargo to Rab11-endosomes and for capture of endosomes at the apical initiation site. This role in polarity utilizes the short intracellular domain but is independent of CD13 peptidase activity.

scholarly journals LKB1 and AMPK maintain epithelial cell polarity under energetic stress

2007 ◽  
Vol 177 (3) ◽  
pp. 387-392 ◽  
Author(s):  
Vincent Mirouse ◽  
Lance L. Swick ◽  
Nevzat Kazgan ◽  
Daniel St Johnston ◽  
Jay E. Brenman
Keyword(s):  
Tumor Suppressor ◽  
Cell Polarity ◽  
Growth Control ◽  
Epithelial Polarity ◽  
Energy Status ◽  
Ampk Signaling ◽  
Cellular Energy ◽  
Energetic Stress ◽  
Stress Dependent

LKB1 is mutated in both familial and spontaneous tumors, and acts as a master kinase that activates the PAR-1 polarity kinase and the adenosine 5′monophosphate–activated kinase (AMPK). This has led to the hypothesis that LKB1 acts as a tumor suppressor because it is required to maintain cell polarity and growth control through PAR-1 and AMPK, respectively. However, the genetic analysis of LKB1–AMPK signaling in vertebrates has been complicated by the existence of multiple redundant AMPK subunits. We describe the identification of mutations in the single Drosophila melanogaster AMPK catalytic subunit AMPKα. Surprisingly, ampkα mutant epithelial cells lose their polarity and overproliferate under energetic stress. LKB1 is required in vivo for AMPK activation, and lkb1 mutations cause similar energetic stress–dependent phenotypes to ampkα mutations. Furthermore, lkb1 phenotypes are rescued by a phosphomimetic version of AMPKα. Thus, LKB1 signals through AMPK to coordinate epithelial polarity and proliferation with cellular energy status, and this might underlie the tumor suppressor function of LKB1.

scholarly journals Versican gene expression in human articular cartilage and comparison of mRNA splicing variation with aggrecan

1993 ◽  
Vol 291 (2) ◽  
pp. 361-367 ◽  
Author(s):  
J Grover ◽  
P J Roughley
Keyword(s):  
Alternative Splicing ◽  
Articular Cartilage ◽  
Regulatory Protein ◽  
Mrna Splicing ◽  
Human Articular Cartilage ◽  
Complement Regulatory Protein ◽  
Mature Adult ◽  
Epidermal Growth ◽  
Egf Domain

The chondrocytes in human articular cartilage from subjects of all ages express mRNAs for both of the aggregating proteoglycans aggrecan and versican, although the level of expression of versican mRNA is much lower than that of aggrecan mRNA. Aggrecan shows alternative splicing of the epidermal growth factor (EGF)-like domain within its C-terminal globular region, but there is no evidence for a major difference in situ in the relative expression of this domain with age. At all ages studied from birth to the mature adult, a greater proportion of transcripts lacked the EGF domain. The relative proportions of the two transcripts did not change upon culture and passage of isolated chondrocytes. In contrast, the neighbouring complement regulatory protein (CRP)-like domain was predominantly expressed irrespective of age, but cell culture did result in variation of the splicing of this domain. Versican possesses two EGF-like domains and one CRP-like domain, but at all ages the three domains were predominantly present in all transcripts. This situation persisted upon culture and passage of the chondrocytes. Thus, unlike aggrecan, the versican expressed by human articular cartilage does not appear to undergo alternative splicing of its C-terminal globular region, either in cartilage in situ or in chondrocytes in culture.

scholarly journals G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity

2018 ◽  
Vol 6 (4) ◽  
pp. 28 ◽  
Author(s):  
Daniel Matúš ◽  
Simone Prömel
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
G Proteins ◽  
Cell Polarity ◽  
Protein Activity ◽  
Independent Manner ◽  
C Elegans ◽  
Downstream Effectors ◽  
Complex Signaling ◽  
G Protein Coupled

Many vital processes during C. elegans development, especially the establishment and maintenance of cell polarity in embryogenesis, are controlled by complex signaling pathways. G protein-coupled receptors (GPCRs), such as the four Frizzled family Wnt receptors, are linchpins in regulating and orchestrating several of these mechanisms. However, despite being GPCRs, which usually couple to G proteins, these receptors do not seem to activate classical heterotrimeric G protein-mediated signaling cascades. The view on signaling during embryogenesis is further complicated by the fact that heterotrimeric G proteins do play essential roles in cell polarity during embryogenesis, but their activity is modulated in a predominantly GPCR-independent manner via G protein regulators such as GEFs GAPs and GDIs. Further, the triggered downstream effectors are not typical. Only very few GPCR-dependent and G protein-mediated signaling pathways have been unambiguously defined in this context. This unusual and highly intriguing concept of separating GPCR function and G-protein activity, which is not restricted to embryogenesis in C. elegans but can also be found in other organisms, allows for essential and multi-faceted ways of regulating cellular communication and response. Although its relevance cannot be debated, its impact is still poorly discussed, and C. elegans is an ideal model to understand the underlying principles.

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