Yes-associated protein is involved in proliferation and differentiation during postnatal liver development

Abstract

It is known that the liver undergoes size increase and differentiation simultaneously during the postnatal period. Cells in the liver undergo a period of well-controlled proliferation to achieve the adult liver-to-body weight ratio. The postnatal liver growth is also accompanied by simultaneous hepatic differentiation. However, the mechanisms of liver size regulation and differentiation are not completely clear. Herein we report that yes-associated protein (Yap), the downstream effector of the Hippo Kinase signaling pathway, plays a role in liver size regulation and differentiation during the postnatal liver growth period. Postnatal liver growth was studied in C57BL/6 mice over a time course of postnatal days (PND) 0- 30. Analysis of nuclear Yap by Western blot indicated peak Yap activation between PND15–20, which coincided with increased cyclin D1 expression and liver cell proliferation. Analysis of postnatal liver development in Yap+/− mice revealed a significant decrease in the liver-to-body weight ratio compared with Yap+/+ mice at PND15 and -30. Yap+/− mice exhibited a significant decrease in postnatal liver cell proliferation, but no change in apoptosis was observed. Furthermore, global gene expression analysis of Yap+/− livers revealed a role of Yap in regulation of genes involved in bile acid metabolism, retinoic acid metabolism, ion transport, and extracellular matrix proteins. Taken together, these data indicate that Yap plays a role in both cell proliferation and possibly in hepatic differentiation during postnatal liver development.

Lats2 is critical for the pluripotency and proper differentiation of stem cells

“…15,43 More recently, it has been suggested that Yap may actually play a positive role in hepatocyte differentiation. 44 In that regard, the phenotypes described here for Lats2 À / À ESCs (failure to maintain stemness and inability to differentiate into mature hepatocytes) are contrary to those observed in response to Yap hyperactivation. Importantly, inhibition of Yap activity failed to rescue the transcriptional defect of Lats2 À / À ESCs (Figure 7c).…”

The Hippo pathway in intestinal regeneration and disease

“…The role of Hippo signalling in liver development is further supported by evidence that the level of nuclear YAP1 correlates with cyclin D1 expression and hepatocyte proliferation during postnatal development in mice 172 . Mice with liver-specific Yap1 deficiency have smaller livers and a reduced hepatocyte proliferation rate compared with wild-type mice 169 .…”

A micro-RNA expression signature for human NAFLD progression

“…Another 48 targets are predicted to pair with miR-34a and miR-301a, which exhibited similar monotonic increases in expression with NAFLD progression. Targets of miR-375 in the liver include astrocyte elevated gene-1 (AEG-1) [65] and yes-associated protein (YAP) [66], the former having a role in mediating steatosis [67] and the later a mediator of hepatic proliferation and differentiation [68]. …”