The Cdc42 GEF Intersectin 2 controls mitotic spindle orientation to form the lumen during epithelial morphogenesis.
Epithelial organs are made of tubes and cavities lined by a monolayer of polarized cells that enclose the central lumen. Lumen formation is a crucial step in the formation of epithelial organs. The Rho guanosine triphosphatase (GTPase) Cdc42, which is a master regulator of cell polarity, regulates the formation of the central lumen in epithelial morphogenesis. However, how Cdc42 is regulated during this process is still poorly understood. Guanine nucleotide exchange factors (GEFs) control the activation of small GTPases. Using the three-dimensional Madin-Darby canine kidney model, we have identified a Cdc42-specific GEF, Intersectin 2 (ITSN2), which localizes to the centrosomes and regulates Cdc42 activation during epithelial morphogenesis. Silencing of either Cdc42 or ITSN2 disrupts the correct orientation of the mitotic spindle and normal lumen formation, suggesting a direct relationship between these processes. Furthermore, we demonstrated this direct relationship using LGN, a component of the machinery for mitotic spindle positioning, whose disruption also results in lumen formation defects.
Rodriguez-Fraticelli
Alejo E
AE
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain.
Vergarajauregui
Silvia
S
Eastburn
Dennis J
DJ
Datta
Anirban
A
Alonso
Miguel A
MA
Mostov
Keith
K
Martín-Belmonte
Fernando
F
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D009024:Morphogenesis / Q000502:physiology; D034622:RNA Interference; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism / Q000648:ultrastructure*; D014404:Tubulin / Q000032:analysis; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D020662:Guanine Nucleotide Exchange Factors; D014404:Tubulin; D020764:cdc42 GTP-Binding Protein