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DiGeorge syndrome (DGS) is the most common microdeletion syndrome, and is characterized by congenital cardiac, craniofacial and immune system abnormalities. The cardiac defects in DGS patients include conotruncal and ventricular septal defects. Although the etiology of DGS is critically regulated by  TBX1  gene, the molecular pathways underpinning  TBX1 's role in heart development are not fully understood. In this study, we characterized heart defects and downstream signaling in the zebrafish  tbx1 −/−   mutant, which has craniofacial and immune defects similar to DGS patients. We show that  tbx1 −/−   mutants have defective heart looping, morphology and function. Defective heart looping is accompanied by failure of cardiomyocytes to differentiate normally and failure to change shape from isotropic to anisotropic morphology in the outer curvatures of the heart. This is the first demonstration of  tbx1 's role in regulating heart looping, cardiomyocyte shape and differentiation, and may explain how Tbx1 regulates conotruncal development in humans. Next we elucidated  tbx1 's molecular signaling pathway guided by the cardiac phenotype of  tbx1 −/−   mutants. We show for the first time that  wnt11r  (wnt11 related), a member of the non-canonical Wnt pathway, and its downstream effector gene  alcama  ( a ctivated  l eukocyte  c ell  a dhesion  m olecule  a)  regulate heart looping and differentiation similarly to  tbx1 . Expression of both  wnt11r  and  alcama  are downregulated in  tbx1 −/−   mutants. In addition, both  wnt11r   −/−  mutants and  alcama  morphants have heart looping and differentiation defects similar to  tbx1 −/−   mutants. Strikingly, heart looping and differentiation in  tbx1 −/−   mutants can be partially rescued by ectopic expression of  wnt11r  or  alcama , supporting a model whereby heart looping and differentiation are regulated by  tbx1  in a linear pathway through  wnt11r  and  alcama . This is the first study linking  tbx1  and non-canonical Wnt signaling and extends our understanding of DGS and heart development.

DiGeorge Syndrome Gene tbx1 Functions through wnt11r to Regulate Heart Looping and Differentiation