Smad5 is essential for left-right asymmetry in mice

Left-Eight (L-R) asymmetry of the vertebrate body plan is established from an originally morphologically symmetric embryo. Recent studies have implica ted several TGF-beta family signaling proteins (i.e., nodal, lefty-1, lefty -2, activin receptor type IIB, and Smad2) in L-R axis determination in the mouse. However, the genetic pathways underlying L-R patterning are still un clear. Smad5 is a downstream component in the TGF-beta family signaling cas cade, and lack of Smad5 results in embryonic lethality between E9.5 and E11 .5. In this report, we demonstrate that Smad5 mutant embryos have defects i n heart looping and embryonic turning which are the first signs of L-R asym metry in mice. To gain more insights into the molecular basis of the latera lity defects in the Smad5-deficient embryos, we examined the expression of lefty-1, lefty-2, nodal, and Pitx2 since the asymmetric expression of these genes always closely correlates with the direction of heart looping and em bryonic turning. In the absence of Smad5, lefty-1 was expressed at very low or undetectable levels, while nodal, lefty-2 and Pitx2 were expressed bila terally. These data suggest that Smad5 is upstream of lefty-1, nodal, and l efty-2, and as a consequence also of Pitx2, and Smad5 is essential for L-R axis determination. (C) 2000 Academic Press.