Local retinoid signaling coordinates forebrain and facial morphogenesis bymaintaining FGF8 and SHH

Correlations between facial anomalies and brain defects are well characteri zed throughout the clinical literature, yet a developmental basis for this association has not been identified. We demonstrate that the frontonasal pr ocess, which gives rise to the mid- and upper face, and the forebrain are l inked early in their morphogenesis by a local retinoid signaling event that maintains the expression of key regulatory molecules. First, we show that aldehyde dehydrogenase 6, which synthesizes the ligand, retinoic acid, is l ocalized to the ventral epithelium of the presumptive frontonasal process o f chick embryos. At least two retinoid receptors are expressed in adjacent populations of mesenchyme. Second, using synthetic pan-specific retinoid an tagonists, we transiently inhibit the ability of retinoid receptors to bind retinoic acid in the rostral head and we generate embryos with a hypoplast ic forebrain, fused eyes, and no frontonasal process-derived structures suc h as the upper beak. These defects are not due to eliminating mesenchymal p rogenitors, as neural crest cells still migrate into the frontonasal proces s, despite disruptions to retinoid signaling. Rather, these malformations r esult from loss of fibroblast growth factor 8 and sonic hedgehog expression , which leads to increased programmed cell death and decreased proliferatio n in the forebrain and frontonasal process. Most significantly, we can resc ue the morphological defects by re-introducing retinoic acid, or fibroblast growth factor and sonic hedgehog proteins into antagonist-treated embryos. We propose that the local source of retinoic acid in the rostral head init iates a regulatory cascade that coordinates forebrain and frontonasal proce ss morphogenesis.