| The Nodal signaling pathway is an evolutionarily conserved TGF-beta-like pathway that governs several critical steps of animal development, including formation of the node, an important signaling center in the early embryo, induction of the mesoderm and endoderm germ layers, and proper asymmetric positioning of the internal organs. Precise regulation of this potent signaling pathway is crucial for its roles in development. We describe two methods of Nodal pathway regulation, one intrinsic and one extrinsic, during early zebrafish development. Using the novel midway mutation of the transcription factor FoxH1, we have developed a model of mesendoderm patterning based on the combinatorial activities of three Nodal transcriptional effectors. This model, which posits that different combinations of these transcription factors dictate the fates of mesendoderm subpopulations, represents a level of Nodal signaling regulation intrinsic to the pathway. Another mutant, called flanders, lies in a putative structural component of motile cilia and disrupts proper asymmetric organ positioning by aberrantly initiating earlier asymmetric activation of the Nodal pathway at Kupffer's vesicle (KV), the zebrafish organ of asymmetry. Whereas many laterality mutants that affect cilia motility also cause embryonic kidney cysts, flanders homozygotes are rarely cystic, suggesting that the flanders gene product is more crucial for cilia motility in KV and not in the kidney. This extrinsic method of Nodal pathway regulation and the intrinsic one revealed by the midway mutation reflect the still-growing list of regulatory mechanisms required for proper control of Nodal signaling in development. |
