Regulation of Head Size by the Extreme Anterior Domain: A Target for Microcephaly

The characteristic size and shape of brain and face in each species suggests that these aspects of head development are coordinately controlled. We show that in Xenopus this control includes signaling activity of the conserved Extreme Anterior Domain (EAD). Extirpation of the EAD truncates facial cartilages derived from the first, second and third neural crest streams, and surprisingly, also reducing forebrain and midbrain size, indicating that the EAD extends long-range organizing function across multiple tissues of the developing head. Part of this function depends on the beta-catenin Wnt inhibitors Frzb and Crescent that are produced by the EAD, since their EAD-specific loss of function (LOF) is associated with reduction of facial cartilages and brain. These data, together with transgenic reporter analysis indicate that the EAD has a signaling range of approximately 40 cell diameters, with activity present by the end of neurulation. Targets of EAD signaling include pharyngeal arch regulatory gene expression, as well as cell proliferation in neural crest, forebrain and midbrain. Our findings identify a signaling mechanism that ensures coordinate development of multiple tissues contributing to the head. The study implies that disruption of EAD organizer activity may underlie disorders such as microcephaly, where anomalies are observed in both brain size and the facial skeleton.