title: Distance between AER and ZPA is defined by feed-forward loop and is stabilized by their feedback loop in vertebrate limb bud.
abstract: In the development of organs, multiple morphogen sources are often involved, and interact with each other. For example, the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) are major morphogen sources in the limb bud formation of vertebrates. Fgf expression in the AER and Shh expression in the ZPA are maintained by their positive feedback regulation mediated by diffusible molecules, FGF and SHH. A recent experimental observation suggests that the FGF-signal regulates the Shh expression in a feed-forward manner with activation and repression regulatory pathways. We study the coupled dynamics of Shh expression in the ZPA and Fgf expression in the AER, and the relationship of the relative position between AER and ZPA. We first show that with the feed-forward regulation only, the peak of ZPA activity can be formed distant from the AER as observed experimentally. Then, we clarify that the robustness of the ZPA spatial pattern to changes in system parameters is enhanced by adding the feedback regulation between the AER and the ZPA. Furthermore, sensitivity analysis shows that there exists the optimal feedback strength where the robustness is the most improved.
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirashima
authors.forename: Yoh
authors.initials: Y
authors.lastname: Iwasa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morishita
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology; D004475:Ectoderm / Q000378:metabolism*; D004627:Embryonic Induction; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D053823:Hedgehog Proteins / Q000378:metabolism; D018878:Limb Buds / Q000196:embryology*; D008648:Mesoderm / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014018:Tissue Distribution / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014714:Vertebrates / Q000196:embryology* / Q000235:genetics / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D015534:Trans-Activators; D005346:Fibroblast Growth Factors