IGF signaling between blastema and wound epidermis is required for fin regeneration

Abstract

In mammals, the loss of a limb is irreversible. By contrast, urodele amphibians and teleost fish are capable of nearly perfect regeneration of lost appendages. This ability depends on direct interaction between the wound epithelium and mesenchymal progenitor cells of the blastema. It has been known for decades that contact between the wound epithelium and the underlying blastema is essential for successful regeneration. However, the underlying mechanisms are poorly understood. Here, we show that upon amputation the blastema induces expression of the ligand Igf2b, which then activates IGF signaling specifically in cells of the adjacent apical epithelium. Inhibition of IGF signaling by either morpholino antisense technology, or by specific chemical inhibitors of Igf1 receptor function NVP-AEW541 and NVP-ADW742, impairs fin regeneration. At the cellular level, this block in regeneration is reflected by a lack of the distinctive basal epithelium, increased apoptosis in the wound epidermis and reduced proliferation of blastema cells. Furthermore, induction of the blastemal and wound epidermal markers cannot be supported in the absence of IGF signaling. These data provide evidence that Igf2b expressed in the blastema promotes the properties of the adjacent wound epidermis, which subsequently are necessary for blastema function. Thus, IGF signaling upregulated upon fin amputation represents a signal from the blastema to the wound epithelium, a crucial step in appendage regeneration.

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

“…Although the role of IGF signaling in regulating normal growth and development is well established, it has only recently become evident that the IGF signaling pathway is often co-opted in various adaptive responses. For example, IGF signaling is increased and has a role in the exercise-induced skeletal muscle hypertrophy in mammals, 51 in fin regeneration upon amputation in zebrafish, 52 and in catch-up growth during re-oxygenation in zebrafish. 53 The results of the present study, along with those mentioned above, suggest that co-option of the ubiquitous IGF signaling pathway in regulating plastic changes of specific tissues in response to environmental factors may be a common theme.…”

A transgenic zebrafish model of targeted oocyte ablation and de novo oogenesis

“…The robust capacity of the zebrafish (Danio rerio) to regenerate fins, neural tissues (retinal cells, optic nerves, spinal cord), and cardiac muscle has led to the widespread use of this model species for tissue and organ regeneration studies (Chablais and Jazwinska, 2010;Jopling et al, 2010;McCurley and Callard, 2010;Cameron, 2000;Poss et al, 2002Poss et al, , 2003Tawk et al, 2002;Lien et al, 2006;Sherpa et al, 2008). The innate regenerative capability of this species, combined with its relative ease of genetic manipulation, has consequently led to many novel insights into the molecular and cellular regulation of tissue regeneration (Curado et al, 2007(Curado et al, , 2008Davison et al, 2007;Pisharath, 2007;Pisharath et al, 2007;Moss et al, 2009;Pisharath and Parsons, 2009;Zhao et al, 2009).…”

Tissue regeneration after injury in adult zebrafish: The regenerative potential of the caudal fin

“…Genes and cell-signaling pathways that are involved in zebrafish fin regeneration have been previously characterized (Laforest et al, 1998;Tawk et al, 2000;Quint et al, 2002;Padhi et al, 2004;Smith et al, 2006;Jazwinska et al, 2007;Stoick-Cooper et al, 2007a, b;Wills et al, 2008;Yin et al, 2008;Chablais and Jazwinska, 2010). For example, Whitehead et al (2005) reported that the expression of fgf20a, a gene that encodes a member of the fibroblast growth factor family, plays important roles in the initiation of fin regeneration, and that decreases in fgf20a expression result in inhibition of fin regeneration.…”