437회 Roles for Bmp, Fgf and Wnt Signaling in Liver Development L

437회 

연사:  신 동 헌, University of California, San Francisco (UCSF)

제목: Roles for Bmp, Fgf and Wnt Signaling in Liver Development

Abstract 

The Bmp and Fgf signaling pathways have been implicated in liver specification.  In vitro mouse and chick explant culture studies have shown that Bmp from the septum transversum mesenchyme and Fgf from the cardiac mesoderm are required for liver specification.  Using genetic tools in in vivo studies, we confirmed the role of Bmp and Fgf in liver specification in zebrafish [1].  In addition to Bmp and Fgf signaling, Wnt signaling is also required for liver specification.  From a forward-genetic screen, we discovered that Wnt signaling mediated by Wnt2bb, which is expressed in the lateral plate mesoderm, is required for liver specification [2].  In addition, we have recently found that Wnt signaling, but not Bmp or Fgf signaling, is sufficient to induce liver specification and subsequent hepatocyte differentiation in non-hepatic endoderm.  This finding allowed us to investigate hepatic competence.  Hepatic competence, or the ability to respond to hepatic inducing signals, is regulated by a number of transcription factors broadly expressed in the endoderm.  However, extrinsic signals might also regulate hepatic competence as suggested by tissue explant studies.  Here, we present genetic evidence that Fgf signaling regulates hepatic competence.  First, we show that the endoderm posterior to the liver-forming region retains hepatic competence.  Using transgenic zebrafish lines that overexpress hepatic inducing signals following heat-shock, we found that Wnt8a overexpression can induce liver gene expression in endodermal cells that otherwise express Pdx1, a pancreas and intestinal bulb marker.  These manipulations result in the appearance of ectopic hepatocytes in the intestinal bulb.  Second, by overexpressing Wnt8a at various stages, we found that as embryos develop the extent of the endodermal region retaining hepatic competence is gradually reduced.  Last, using gain- and loss-of-function approaches, we found that Fgf10a signaling regulates this gradual restriction of the hepatic-competent domain.  These data provide the first in vivo evidence that endodermal cells outside the liver-forming region retain hepatic competence and demonstrate that an extrinsic signal, Fgf10a, negatively regulates hepatic competence.

1.         Shin, D., et al., Bmp and Fgf signaling are essential for liver specification in zebrafish. Development, 2007. 134(11): p. 2041-50.

2.         Ober, E.A., et al., Mesodermal Wnt2b signalling positively regulates liver specification. Nature, 2006. 442(7103): p. 688-91.