Two nodal-responsive enhancers control left-right asymmetric expression of Nodal.

Asymmetric expression of Nodal in the lateral plate mesoderm (LPM) plays the major role in left-right (L-R) patterning. A Nodal-responsive enhancer located in the intron 1 (ASE) regulates asymmetric Nodal expression, but it is unknown how Nodal expression is initiated in the left LPM. Here, we have identified a second asymmetric enhancer (left side-specific enhancer, LSE) in the upstream region of mouse Nodal gene. LSE is also located in the corresponding region of human NODAL. L-R specificity of LSE is affected by iv and inv mutations. The requirement of a conserved FoxH1-binding sequence for LSE activity and the dependence of LSE activity on Nodal coreceptor Cryptic indicate that LSE is activated by Nodal signal. However, the mutant mouse lacking LSE does not show obvious L-R patterning defects. These results suggest that Nodal expression in the left LPM is induced by a combination of two Nodal-responsive autoregulatory enhancers, ASE and LSE. Copyright 2005 Wiley-Liss, Inc.