Yap1, transcription regulator in the Hippo signaling pathway, is required for Xenopus limb bud regeneration.
The Hippo signaling pathway is conserved from insects to mammals and is important for multiple processes, including cell proliferation, apoptosis and tissue homeostasis. Hippo signaling is also crucial for regeneration, including intercalary regeneration, of the whole body in the flatworm and of the leg in the cricket. However, its role in vertebrate epimorphic regeneration is unknown. Therefore, to identify principles of regeneration that are conserved among bilaterians, we investigated the role of Hippo signaling in the limb bud regeneration of an anuran amphibian, Xenopus laevis. We found that a transcription factor, Yap1, an important downstream effector of Hippo signaling, is upregulated in the regenerating limb bud. To evaluate Yap1׳s function in limb bud regeneration, we made transgenic animals that expressed a dominant-negative form of Yap under a heat-shock promoter. Overexpression of a dominant-negative form of Yap in tadpoles reduced cell proliferation, induced ectopic apoptosis, perturbed the expression domains of limb-patterning genes including hoxa13, hoxa11, and shh in the regenerating limb bud. Transient expression of a dominant-negative Yap in transgenic tadpoles also caused limb bud regeneration defects, and reduced intercalary regeneration. These results indicate that Yap1 has a crucial role in controlling the limb regenerative capacity in Xenopus, and suggest that the involvement of Hippo signaling in regeneration is conserved between vertebrates and invertebrates. This finding provides molecular evidence that common principles underlie regeneration across phyla, and may contribute to the development of new therapies in regenerative medicine.
Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aramaki-Aza-Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan.
Shinichi
S
Hayashi
Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aramaki-Aza-Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan.
Koji
K
Tamura
Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aramaki-Aza-Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan. Electronic address: yokoyoko@m.tohoku.ac.jp.
Hitoshi
H
Yokoyama
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D019521:Body Patterning; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018878:Limb Buds / Q000196:embryology / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012038:Regeneration; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D029867:Xenopus Proteins / Q000235:genetics* / Q000502:physiology*; D014982:Xenopus laevis / Q000196:embryology*; D000091102:YAP-Signaling Proteins
D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; C561677:YAP protein, Xenopus; D000091102:YAP-Signaling Proteins
Hippo pathway; Intercalation; Limb bud regeneration; Yap1