AbstractThe transcriptional regulator RERE/Atrophin‐2 (RERE) is required for the normal patterning of the early vertebrate embryo, including the central nervous system, pharyngeal arches, and limbs. Consistent with a role as a transcriptional corepressor, RERE binds histone deacetylase 1 and 2 (HDAC1/2), and orphan nuclear receptors such as Tlx. Here, we identify the zebrafishbabyface(bab) as a mutant inrereaand show that it interacts genetically withfibroblast growth factor 8(fgf8). We suggest that this finding is largely due to its interactions with HDAC, because genetic or pharmacological disruptions of HDAC phenocopy many features of thebabmutant. Furthermore, removing the functions of either REREa or HDAC synergizes with loss of Fgf8 function to disrupt posterior mesoderm formation during somitogenesis, midbrain–hindbrain boundary maintenance, and pharyngeal cartilage development. Together, these results reveal novel in vivo roles for REREa in HDAC‐mediated regulation of Fgf signaling. We present a model for RERE‐dependent patterning in which tissue‐specific transcriptional repression, by means of an REREa‐HDAC complex, modulates growth factor signaling during embryogenesis. Developmental Dynamics 236:1891–1904, 2007. © 2007 Wiley‐Liss, Inc.