Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites

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Abstract
Elaborate metamerism in vertebrate somitogenesis is based on segmental gene expression in the anterior presomitic mesoderm (PSM). Notch signal pathways with Notch ligands Dll1 and Dll3, and the transcription factor Mesp2 are implicated in the rostrocaudal patterning of the somite. We have previously shown that changes in the Mesp2 expression domain from a presumptive one somite into a rostral half somite results in differential activation of two types of Notch pathways, dependent or independent of presenilin 1 (Psen1), which is a Notch signal mediator. To further refine our hypothesis, we have analyzed genetic interactions between Dll1, Dll3, Mesp2 and Psen1, and elucidated the roles of Dll1- and Dll3-Notch pathways, with or without Psen1, in rostrocaudal patterning. Dll1 and Dll3 are co-expressed in the PSM and so far are considered to have partially redundant functions. We find in this study that positive and negative feedback loops comprising Dll1 and Mesp2 appear to be crucial for this patterning, and Dll3 may be required for the coordination of the Dll1-Mesp2 loop. Additionally, our epistatic analysis revealed that Mesp2 affects rostrocaudal properties more directly than Dll1 or Dll3. Finally, we find that Psen1 is involved differently in the regulation of rostral and caudal genes. Psen1 is required for Dll1-Notch signaling for activation of Dll1, while the Psen1-independent Dll3-Notch pathway may counteract the Psen1-dependent Dll1-Notch pathway. These observations suggest that Dll1 and Dll3 may have non-redundant, even counteracting functions. We conclude from our analyses that Mesp2 functions as a central mediator of such Notch pathways and regulates the gene expression required for rostrocaudal patterning of somites.