Early requirement of Hyaluronan for tail regeneration in Xenopus tadpoles.
Tail regeneration in Xenopus tadpoles is a favorable model system to understand the molecular and cellular basis of tissue regeneration. Although turnover of the extracellular matrix (ECM) is a key event during tissue injury and repair, no functional studies to evaluate its role in appendage regeneration have been performed. Studying the role of Hyaluronan (HA), an ECM component, is particularly attractive because it can activate intracellular signaling cascades after tissue injury. Here we studied the function of HA and components of the HA pathway in Xenopus tadpole tail regeneration. We found that transcripts for components of this pathway, including Hyaluronan synthase2 (HAS2), Hyaluronidase2 and its receptors CD44 and RHAMM, were transiently upregulated in the regenerative bud after tail amputation. Concomitantly, an increase in HA levels was observed. Functional experiments using 4-methylumbelliferone, a specific HAS inhibitor that blocked the increase in HA levels after tail amputation, and transgenesis demonstrated that the HA pathway is required during the early phases of tail regeneration. Proper levels of HA are required to sustain proliferation of mesenchymal cells in the regenerative bud. Pharmacological and genetic inhibition of GSK3beta was sufficient to rescue proliferation and tail regeneration when HA synthesis was blocked, suggesting that GSK3beta is downstream of the HA pathway. We have demonstrated that HA is an early component of the regenerative pathway and is required for cell proliferation during the early phases of Xenopus tail regeneration. In addition, a crosstalk between HA and GSK3beta signaling during tail regeneration was demonstrated.
Contreras
Esteban G
EG
Center for Aging and Regeneration, Center for Cell Regulation and Pathology, Faculty of Biological Sciences, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile.
Gaete
Marcia
M
Sánchez
Natalia
N
Carrasco
Héctor
H
Larraín
Juan
J
D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000235:genetics / Q000378:metabolism*; D006923:Hymecromone / Q000031:analogs & derivatives / Q000378:metabolism; D007814:Larva / Q000033:anatomy & histology / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013623:Tail / Q000033:anatomy & histology / Q000502:physiology*; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000033:anatomy & histology / Q000502:physiology
C000623051:Hmmr protein, Xenopus; D018960:Hyaluronan Receptors; D008869:Microtubule-Associated Proteins; D029867:Xenopus Proteins; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491096:Has2 protein, Xenopus; D000076002:Hyaluronan Synthases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3