Cellular mechanisms of heart morphogenesis and lumen formation in Drosophila. Georg Vogler¹, Jiandong Liu², Timothy W Iafe³, Rolf Bodmer¹. 1) Development and Aging, Sanford Burnham Medical Research Institute, La Jolla, CA; 2) University of North Carolina, School of Medicine, Chapel Hill, NC; 3) New York University, School of Medicine, New York, NY.

   The Drosophila embryonic heart is a key model system for understanding heart specification. Our previous studies indicate that heart morphogenesis requires Slit/Robo signaling, a function conserved in vertebrates. The mechanisms by which these and other signals control heart formation are still unknown. Due to its role in membrane dynamics, we investigated the role of the small GTPase Cdc42 during Drosophila heart development and found it to be required for cardiac cell alignment and heart tube formation. Mutant or constitutively active Cdc42 in the developing heart causes improper cardioblast alignment and formation of multiple lumina, suggesting that Cdc42 is required during discrete steps of cardiogenesis. Cell polarity and filopodia dynamics are unaffected by loss of Cdc42, therefore Cdc42 might have a different role during heart morphogenesis. To understand the regulation of Cdc42 and to identify new genetic interactors, we performed a genetic screen for modifiers of Cdc42. We identified the tyrosine kinase Abelson (Abl), and the non-muscle myosin-II zipper to strongly interact with Cdc42. Abl itself shows a requirement for coordinated heart tube assembly, and Zipper exhibits a dynamic localization pattern during cardiogenesis, which depends on Cdc42 function, but is independent of Slit/Robo. Activation of the formin-like protein Diaphanous (Dia) produced defects similar to activated Cdc42, indicating that control of cell shape changes is a key regulatory step during heart morphogenesis. Our data suggest a novel mechanism of cardiac morphogenesis involving Abl, Cdc42, Dia and Zip acting in a common pathway during cardiac cell shape changes and orchestrated heart lumen formation.