Odd skipped related 1 is a negative feedback regulator of nodal-induced endoderm development

Early embryo patterning is orchestrated by tightly regulated morphogen gradients. The Nodal morphogen patterns the mesendoderm, giving rise to all endoderm and head and trunk mesoderm. High Nodal concentrations favor endoderm differentiation while lower promote mesoderm differentiation. Nodal signaling is controlled by both positive and negative feedback regulation to ensure robust developmental patterning.

Here we identify odd skipped related 1 (osr1), a zinc finger transcription factor, as a new element in Nodal feedback regulation affecting endoderm development. We show that osr1 expression in zebrafish germ ring mesendoderm requires Nodal signaling; osr1 expression was lost in embryos lacking Nodal signaling. Conversely, osr1 expression was ectopically induced by the activation of Nodal signaling. Furthermore we demonstrate that osr1 responds directly to Nodal signaling. Additionally, osr1 knockdown generated excess endoderm cells marked by sox32 expression while expression of osr1 mRNA was not affected in sox32-deficient embryos.

Our findings identify osr1 as a Nodal-induced, negative feedback regulator of Nodal signaling that acts at the earliest stages of endoderm differentiation to limit the number of endoderm progenitors. As such, we propose that osr1 represents a novel network motif controlling the output of Nodal signaling to regulate mesendoderm patterning.