Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1.
Orientation of spindles and cell division planes during development of many species ensures that correct cell-cell contacts are established, which is vital for proper tissue formation. This is a tightly regulated process involving a complex interplay of various signals. The molecular mechanisms underlying several of these pathways are still incompletely understood. Here, we identify the signaling cascade of the C. elegans latrophilin homolog LAT-1, an essential player in the coordination of anterior-posterior spindle orientation during the fourth round of embryonic cell division. We show that the receptor mediates a G protein-signaling pathway revealing that G-protein signaling in oriented cell division is not solely GPCR-independent. Genetic analyses showed that through the interaction with a Gs protein LAT-1 elevates intracellular cyclic AMP (cAMP) levels in the C. elegans embryo. Stimulation of this G-protein cascade in lat-1 null mutant nematodes is sufficient to orient spindles and cell division planes in the embryo in the correct direction. Finally, we demonstrate that LAT-1 is activated by an intramolecular agonist to trigger this cascade. Our data support a model in which a novel, GPCR-dependent G protein-signaling cascade mediated by LAT-1 controls alignment of cell division planes in an anterior-posterior direction via a metabotropic Gs-protein/adenylyl cyclase pathway by regulating intracellular cAMP levels.
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Antje
A
Müller
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Jana
J
Winkler
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Franziska
F
Fiedler
Institute of Genetics, TU Braunschweig, Braunschweig, Germany.
Tania
T
Sastradihardja
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Claudia
C
Binder
Institute of Genetics, TU Braunschweig, Braunschweig, Germany.
Ralf
R
Schnabel
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Jana
J
Kungel
Core Unit Peptide Technologies, Medical Faculty, Leipzig University, Leipzig, Germany.
Sven
S
Rothemund
Institute of Genetics, TU Braunschweig, Braunschweig, Germany.
Christian
C
Hennig
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Torsten
T
Schöneberg
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Simone
S
Prömel
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D002448:Cell Adhesion / Q000235:genetics; D002455:Cell Division / Q000235:genetics*; D000242:Cyclic AMP / Q000235:genetics; D004625:Embryo, Nonmammalian; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D027283:Large Neutral Amino Acid-Transporter 1; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases