RRC ID 51399
Author Von Stetina SE, Liang J, Marnellos G, Mango SE.
Title Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6.
Journal Mol. Biol. Cell
Abstract 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.
Volume 28(15)
Pages 2042-2065
Published 2017-7-15
DOI 10.1091/mbc.E16-09-0644
PII mbc.E16-09-0644
PMID 28539408
PMC PMC5509419
MeSH Adherens Junctions / metabolism Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / metabolism* Cell Polarity / physiology Cytoskeleton / metabolism Digestive System / growth & development Epithelial Cells / metabolism Epithelium / metabolism Gene Expression Regulation, Developmental / genetics Kinesin / metabolism* Microtubule-Associated Proteins / metabolism Morphogenesis / physiology Structure-Activity Relationship Trans-Activators / metabolism*
IF 3.512
C.elegans tm1425