In summary, our studies demonstrate that Ptdsr is required for normal tissue differentiation, especially during the mid-gestation period when we observed the most severe differentiation delays in several organs of Ptdsr-knockout mice. The multiple defects in tissue differentiation cannot be explained by failure of apoptotic cell clearance, as this process is normal in our Ptdsr-knockout line. This result therefore indicates that Ptdsr has a novel, hitherto unexpected, role in promoting tissue maturation and terminal differentiation. Additional studies with conditionally targeted Ptdsr-deficient mice are required to investigate the role of spatial and temporal Ptdsr expression and function during tissue differentiation.