Left–right asymmetry is established early in embryonic development so that your heart, for example, ends up on the left side of your body. Syndecan-2 is known to be involved in this process by transmitting left–right information from the ectoderm to the adjacent migrating mesoderm during gastrulation, but the mechanism for this was largely unknown. Now, however, Yost's group show that the cytoplasmic domain of syndecan is targeted by protein kinase C (PKC)-γ in right, but not left, ectodermal cells in Xenopus and that this is one of the earliest steps in left–right development, occurring before the appearance of nodal cilia.

In vitro, PKC family members phosphorylate syndecans, so the group hypothesized that a PKC might function in early left–right development. Specific inhibitors and dominant-negative forms of PKC (dnPKC) showed that PKCγ in the ectoderm regulates left–right development during early gastrula stages. Inhibiting PKCγ function specifically in left or right ectodermal lineages indicated that PKCγ is specifically required in cells of the right ectoderm.

Logically, PKCγ substrates should be present in right ectodermal cells. Immunocytochemical analysis of mid-gastrula-stage embryos showed that syndecan-2 was present in the deep layer of ectoderm that interacts with the migrating mesoderm — the sensorial ectoderm. But phosphorylated syndecan-2 was present only in the right sensorial ectoderm, which directly contacts migrating mesoderm.

So, is this phosphorylation of relevance to left–right asymmetry? Syndecan-2 mutants in which either or both of two cytoplasmic phosphoacceptor serine residues were changed to alanines showed reversal of the normal position of the heart in 19% and 41% of cases, respectively, when both sides of the ectoderm were targeted at the same time. When targeted individually with the double mutant, the right-side ectoderm showed greater disruption. The converse experiment, using phosphomimetic mutants, showed that syndecan-2 must be phosphorylated on the right, but non-phosphorylated on the left, for normal left–right development. Finally, PKCγ was shown to be upstream of syndecan-2 in the same pathway because phosphorylation of endogenous syndecan-2 depended on PKCγ and phosphomimetic syndecan-2 overcame the loss of PKCγ activity.

What is unclear at present is how serine phosphorylation influences the inside–out transducing function of syndecan-2 in the ectoderm to enable it to act cell non-autonomously to influence the migrating mesodermal cells. However, there seems to be no shortage of ideas.