The metazoan liver exhibits a remarkable capacity to regenerate lost liver mass without leaving a
scar following partial
hepatectomy (PH). Whilst previous studies have identified components of several different signaling pathways that are essential for activation of hepatocyte proliferation during liver regeneration, the mechanisms that enable such regeneration to occur without accompanying
scar formation remain poorly understood. Here we use the adult zebrafish liver, which can regenerate within two weeks following PH, as a new genetic model to address this important question. We focus on the role of Digestive-organ-expansion-factor (
Def), a
nucleolar protein which has recently been shown to complex with calpain3 (Capn3) to mediate p53 degradation specifically in the nucleolus, in liver regeneration. Firstly, we show that
Def expression is up-regulated in the wild-type liver following
amputation, and that the defhi429/+ heteroozygous mutant (
def+/-) suffers from haploinsufficiency of
Def in the liver. We then show that the expression of pro-inflammatory
cytokines is up-regulated in the
def+/- liver, which leads to distortion of the migration and the clearance of leukocytes after PH.
Transforming growth factor β (TGFβ) signalling is thus activated in the
wound epidermis in
def+/- due to a prolonged inflammatory response, which leads to
fibrosis at the
amputation site. Fibrotic
scar formation in
def+/- is blocked by the over-expression of
Def, by the loss-of-function of p53, and by treatment with anti-
inflammation drug dexamethasone or TGFβ-signalling inhibitor
SB431542. We finally show that the
Def- p53 pathway suppresses fibrotic
scar formation, at least in part, through the regulation of the expression of the pro-inflammatory factor, high-mobility group box 1. We conclude that the novel
Def- p53 nucleolar pathway functions specifically to prevent a
scar formation at the
amputation site in a normal amputated liver.