ErbB2 and ErbB3 regulate amputation-induced proliferation and migration during vertebrate regeneration.
Epimorphic regeneration is a unique and complex instance of postembryonic growth observed in certain metazoans that is usually triggered by severe injury [Akimenko et al., 2003; Alvarado and Tsonis, 2006; Brockes, 1997; Endo et al., 2004]. Cell division and migration are two fundamental biological processes required for supplying replacement cells during regeneration [Endo et al., 2004; Slack, 2007]. However, the connection between the early stimuli generated after injury and the signals regulating proliferation and migration during regeneration remain largely unknown. Here we show that the oncogenes ErbB2 and ErbB3, two members of the EGFR family, are essential for mounting a successful regeneration response in vertebrates. Importantly, amputation-induced progenitor proliferation and migration are significantly reduced upon genetic and/or chemical modulation of ErbB function. Moreover, we also found that NRG1 and PI3K functionally interact with ErbB2 and ErbB3 during regeneration and interfering with their function also abrogates the capacity of progenitor cells to regenerate lost structures upon amputation. Our findings suggest that ErbB, PI3K and NRG1 are components of a permissive switch for migration and proliferation continuously acting across the amputated fin from early stages of vertebrate regeneration onwards that regulate the expression of the transcription factors lef1 and msxB.
Rojas-Muñoz
Agustin
A
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Rajadhyksha
Shibani
S
Gilmour
Darren
D
van Bebber
Frauke
F
Antos
Christopher
C
Rodríguez Esteban
Concepción
C
Nüsslein-Volhard
Christiane
C
Izpisúa Belmonte
Juan Carlos
JC
D000671:Amputation, Surgical; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000235:genetics; D020890:Neuregulin-1 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000502:physiology*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D014714:Vertebrates; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
D018398:Homeodomain Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D014157:Transcription Factors; D029961:Zebrafish Proteins; C507321:LEF1 protein, zebrafish; C460082:msx1b protein, zebrafish