SPC4/PACE4 regulates a TGF beta signaling network during axis formation

In vertebrates, specification of anteroposterior (A/P) and left-right (L/R) axes depends on TGF beta-related signals, including Nodal, Lefty, and BMPs . Endoproteolytic maturation of these proteins is probably mediated by the proprotein convertase SPC1/Furin. In addition, precursor processing may be regulated by related activities such as SPC4 (also known as PACE4). Here, w e show that a proportion of embryos lacking SPC4 develop situs ambiguus com bined with left pulmonary isomerism or complex craniofacial malformations i ncluding cyclopia, or both. Gene expression analysis during early somite st ages indicates that spc4 is genetically upstream of nodal, pitx2, lefty1, a nd lefty2 and perhaps maintains the balance between Nodal and BMP signaling in the lateral plate that is critical for L/R axis formation. Furthermore, genetic interactions between nodal and spc4, together with our analysis of chimeric embryos, strongly suggest that during A/P axis formation, SPC4 ac ts primarily in the foregut. These findings establish an important role for SPC4 in patterning the early mouse embryo.