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Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6

To establish the animal body plan, embryos link the external epidermis to the internal digestive tract. In Caenorhabditis elegans, this linkage is achieved by the arcade cells, which form an epithelial bridge between the foregut and epidermis, but little is known about how development of these three...

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Autores principales: Von Stetina, Stephen E., Liang, Jennifer, Marnellos, Georgios, Mango, Susan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509419/
https://www.ncbi.nlm.nih.gov/pubmed/28539408
http://dx.doi.org/10.1091/mbc.E16-09-0644
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author Von Stetina, Stephen E.
Liang, Jennifer
Marnellos, Georgios
Mango, Susan E.
author_facet Von Stetina, Stephen E.
Liang, Jennifer
Marnellos, Georgios
Mango, Susan E.
author_sort Von Stetina, Stephen E.
collection PubMed
description To establish the animal body plan, embryos link the external epidermis to the internal digestive tract. In Caenorhabditis elegans, this linkage is achieved by the arcade cells, which form an epithelial bridge between the foregut and epidermis, but little is known about how development of these three epithelia is coordinated temporally. The arcade cell epithelium is generated after the epidermis and digestive tract epithelia have matured, ensuring that both organs can withstand the mechanical stress of embryo elongation; mistiming of epithelium formation leads to defects in morphogenesis. Using a combination of genetic, bioinformatic, and imaging approaches, we find that temporal regulation of the arcade cell epithelium is mediated by the pioneer transcription factor and master regulator PHA-4/FoxA, followed by the cytoskeletal regulator and kinesin ZEN-4/MKLP1 and the polarity protein PAR-6. We show that PHA-4 directly activates mRNA expression of a broad cohort of epithelial genes, including junctional factor dlg-1. Accumulation of DLG-1 protein is delayed by ZEN-4, acting in concert with its binding partner CYK-4/MgcRacGAP. Our structure–function analysis suggests that nuclear and kinesin functions are dispensable, whereas binding to CYK-4 is essential, for ZEN-4 function in polarity. Finally, PAR-6 is necessary to localize polarity proteins such as DLG-1 within adherens junctions and at the apical surface, thereby generating arcade cell polarity. Our results reveal that the timing of a landmark event during embryonic morphogenesis is mediated by the concerted action of four proteins that delay the formation of an epithelial bridge until the appropriate time. In addition, we find that mammalian FoxA associates with many epithelial genes, suggesting that direct regulation of epithelial identity may be a conserved feature of FoxA factors and a contributor to FoxA function in development and cancer.
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spelling pubmed-55094192017-09-30 Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6 Von Stetina, Stephen E. Liang, Jennifer Marnellos, Georgios Mango, Susan E. Mol Biol Cell Articles To establish the animal body plan, embryos link the external epidermis to the internal digestive tract. In Caenorhabditis elegans, this linkage is achieved by the arcade cells, which form an epithelial bridge between the foregut and epidermis, but little is known about how development of these three epithelia is coordinated temporally. The arcade cell epithelium is generated after the epidermis and digestive tract epithelia have matured, ensuring that both organs can withstand the mechanical stress of embryo elongation; mistiming of epithelium formation leads to defects in morphogenesis. Using a combination of genetic, bioinformatic, and imaging approaches, we find that temporal regulation of the arcade cell epithelium is mediated by the pioneer transcription factor and master regulator PHA-4/FoxA, followed by the cytoskeletal regulator and kinesin ZEN-4/MKLP1 and the polarity protein PAR-6. We show that PHA-4 directly activates mRNA expression of a broad cohort of epithelial genes, including junctional factor dlg-1. Accumulation of DLG-1 protein is delayed by ZEN-4, acting in concert with its binding partner CYK-4/MgcRacGAP. Our structure–function analysis suggests that nuclear and kinesin functions are dispensable, whereas binding to CYK-4 is essential, for ZEN-4 function in polarity. Finally, PAR-6 is necessary to localize polarity proteins such as DLG-1 within adherens junctions and at the apical surface, thereby generating arcade cell polarity. Our results reveal that the timing of a landmark event during embryonic morphogenesis is mediated by the concerted action of four proteins that delay the formation of an epithelial bridge until the appropriate time. In addition, we find that mammalian FoxA associates with many epithelial genes, suggesting that direct regulation of epithelial identity may be a conserved feature of FoxA factors and a contributor to FoxA function in development and cancer. The American Society for Cell Biology 2017-07-15 /pmc/articles/PMC5509419/ /pubmed/28539408 http://dx.doi.org/10.1091/mbc.E16-09-0644 Text en © 2017 Von Stetina et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Von Stetina, Stephen E.
Liang, Jennifer
Marnellos, Georgios
Mango, Susan E.
Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
title Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
title_full Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
title_fullStr Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
title_full_unstemmed Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
title_short Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
title_sort temporal regulation of epithelium formation mediated by foxa, mklp1, mgcracgap, and par-6
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509419/
https://www.ncbi.nlm.nih.gov/pubmed/28539408
http://dx.doi.org/10.1091/mbc.E16-09-0644
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