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• W2051570658 abstract "The mechanism that regulates embryonic liver morphogenesis remains elusive. Progranulin (PGRN) is postulated to play a critical role in regulating pathological liver growth. Nevertheless, the exact regulatory mechanism of PGRN in relation to its functional role in embryonic liver development remains to be elucidated. In our study, the knockdown of progranulin A (GrnA), an orthologue of mammalian PGRN, using antisense morpholinos resulted in impaired liver morphogenesis in zebrafish (Danio rerio). The vital role of GrnA in hepatic outgrowth and not in liver bud formation was further confirmed using whole-mount in situ hybridization markers. In addition, a GrnA deficiency was also found to be associated with the deregulation of MET-related genes in the neonatal liver using a microarray analysis. In contrast, the decrease in liver size that was observed in grnA morphants was avoided when ectopic MET expression was produced by co-injecting met mRNA and grnA morpholinos. This phenomenon suggests that GrnA might play a role in liver growth regulation via MET signaling. Furthermore, our study has shown that GrnA positively modulates hepatic MET expression both in vivo and in vitro. Therefore, our data have indicated that GrnA plays a vital role in embryonic liver morphogenesis in zebrafish. As a result, a novel link between PGRN and MET signaling is proposed. The mechanism that regulates embryonic liver morphogenesis remains elusive. Progranulin (PGRN) is postulated to play a critical role in regulating pathological liver growth. Nevertheless, the exact regulatory mechanism of PGRN in relation to its functional role in embryonic liver development remains to be elucidated. In our study, the knockdown of progranulin A (GrnA), an orthologue of mammalian PGRN, using antisense morpholinos resulted in impaired liver morphogenesis in zebrafish (Danio rerio). The vital role of GrnA in hepatic outgrowth and not in liver bud formation was further confirmed using whole-mount in situ hybridization markers. In addition, a GrnA deficiency was also found to be associated with the deregulation of MET-related genes in the neonatal liver using a microarray analysis. In contrast, the decrease in liver size that was observed in grnA morphants was avoided when ectopic MET expression was produced by co-injecting met mRNA and grnA morpholinos. This phenomenon suggests that GrnA might play a role in liver growth regulation via MET signaling. Furthermore, our study has shown that GrnA positively modulates hepatic MET expression both in vivo and in vitro. Therefore, our data have indicated that GrnA plays a vital role in embryonic liver morphogenesis in zebrafish. As a result, a novel link between PGRN and MET signaling is proposed. IntroductionThe liver is the largest essential internal organ and has a number of vital functions in the body. The liver parenchyma is largely constituted of hepatocytes (∼80%), and the remaining cells include cholangiocytes, Kupffer cells, stellate cells, and sinusoidal endothelial cells (1Blouin A. Bolender R.P. Weibel E.R. J. Cell Biol. 1977; 72: 441-455Crossref PubMed Scopus (594) Google Scholar). Liver organogenesis is initiated in the endodermal cells of the ventral foregut, which develop competence from the cardiac mesoderm to form hepatoblasts. During the specification stages, the specified hepatoblasts form a liver bud and undergo the hepatic outgrowth process. Hepatic outgrowth is characterized by a large change in the liver bud size that is caused by the rapid proliferation of hepatoblasts. Finally, the hepatoblasts differentiate into functional hepatocytes and cholangiocytes (2Duncan S.A. Mech. Dev. 2003; 120: 19-33Crossref PubMed Scopus (145) Google Scholar, 3Zaret K.S. Nat. Rev. Genet. 2002; 3: 499-512Crossref PubMed Scopus (427) Google Scholar). In studies using chicks and mice, liver organogenesis has been shown to be tightly regulated by growth factors, cytokines, and transcription factors. However, little is known about the genetic requirements of the liver growth process and its regulatory mechanism. The use of knock-out mice has led to the discovery of several genes that are critical for hepatic outgrowth. An example of these critical genes is the met gene that encodes the hepatocyte growth factor receptor that regulates cell migration, proliferation, morphogenesis, and angiogenesis (4Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Nat. Rev. Mol. Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2209) Google Scholar). A knock-out of the met gene in mice results in early embryonic lethality and a reduced liver size in utero (5Bladt F. Riethmacher D. Isenmann S. Aguzzi A. Birchmeier C. Nature. 1995; 376: 768-771Crossref PubMed Scopus (1087) Google Scholar). In addition, growth hormone has been shown to be a liver growth-promoting factor (6Palmiter R.D. Norstedt G. Gelinas R.E. Hammer R.E. Brinster R.L. Science. 1983; 222: 809-814Crossref PubMed Scopus (480) Google Scholar). To investigate novel regulatory factors involved in liver growth, a subtractive hybridization in conjunction with growth hormone administration was performed. This hybridization led to the identification of progranulin (PGRN) 2The abbreviations used are: PGRNprogranulinHCChepatocellular carcinomahpfhours post-fertilizationMOmorpholinoWISHwhole-mount in situ hybridizationPH3phosphohistone H3PCNAproliferating cell nuclear antigendpfdays post-fertilizationEGFPenhanced green fluorescent protein. as a novel growth hormone-regulated growth factor in the liver (7Chen M.H. Li Y.H. Chang Y. Hu S.Y. Gong H.Y. Lin G.H. Chen T.T. Wu J.L. Gen. Comp. Endocrinol. 2007; 150: 212-218Crossref PubMed Scopus (22) Google Scholar).PGRN, also known as epithelin/granulin precursor, acrogranin, proepithelin, and PC cell-derived growth factor, is a pleiotropic autocrine growth factor that contributes to early embryogenesis, the wound healing response, frontotemporal dementia, and tumorigenesis (8He Z. Bateman A. J. Mol. Med. 2003; 81: 600-612Crossref PubMed Scopus (408) Google Scholar, 9Ong C.H. Bateman A. Histol. Histopathol. 2003; 18: 1275-1288PubMed Google Scholar). PGRN is an extracellular glycoprotein that consists of multiple copies of the cysteine-rich granulin motif. Elevated PGRN levels often occur in patients with cancer, and epidemiological studies show that PGRN is overexpressed in 70% of hepatocellular carcinoma (HCC) patients. Overexpression of PGRN promotes the growth and invasion of HCC cells (10Cheung S.T. Wong S.Y. Leung K.L. Chen X. So S. Ng I.O. Fan S.T. Clin. Cancer Res. 2004; 10: 7629-7636Crossref PubMed Scopus (103) Google Scholar). Treatment with a PGRN monoclonal antibody has been shown to block the established HCC tumor growth in a mouse xenotransplantation model (11Ho J.C. Ip Y.C. Cheung S.T. Lee Y.T. Chan K.F. Wong S.Y. Fan S.T. Hepatology. 2008; 47: 1524-1532Crossref PubMed Scopus (99) Google Scholar), which suggests that PGRN is involved in regulating pathological hepatocyte growth. Although the dysregulation of embryonic hepatogenesis signaling has been shown to be associated with hepatocarcinogenesis (12Breuhahn K. Longerich T. Schirmacher P. Oncogene. 2006; 25: 3787-3800Crossref PubMed Scopus (339) Google Scholar), the physiological role of PGRN in hepatogenesis remains unclear.Zebrafish are an ideal model for studying the physiological role of PGRN in hepatogenesis because early stages of liver organogenesis in zebrafish are similar to those observed in mice (13Chu J. Sadler K.C. Hepatology. 2009; 50: 1656-1663Crossref PubMed Scopus (146) Google Scholar). There are four PGRN genes (grnA, grnB, grn1, and grn2) in the zebrafish genome, whereas only one gene encodes PGRN in mammals. According to the syntenic conservation of chromosomal localization, grnA is the orthologue of the mammalian PGRN gene. In zebrafish, the expression of grnA has been observed in the anterior endoderm and the liver primordium from 24 to 120 h post-fertilization (hpf) (14Cadieux B. Chitramuthu B.P. Baranowski D. Bennett H.P. BMC Genomics. 2005; 6: 156Crossref PubMed Scopus (42) Google Scholar), which suggests that grnA might contribute to liver development. In the present study, we knocked down GrnA expression using morpholinos (MOs), which resulted in a small liver phenotype in zebrafish. According to the whole-mount in situ hybridization (WISH) analysis, we determined that the morphological defect was caused by an impaired hepatic outgrowth. Furthermore, a microarray approach combined with in vitro and in vivo examinations revealed that GrnA was an upstream factor of MET signaling in liver growth. Taken together, our findings indicate that GrnA is essential for embryonic liver morphogenesis. In addition, our findings also indicate a possible relationship between PGRN and MET signaling.DISCUSSIONThe dysregulation of embryonic growth factors, receptors, and their downstream signaling components in adulthood has been shown to promote HCC proliferation and invasiveness (12Breuhahn K. Longerich T. Schirmacher P. Oncogene. 2006; 25: 3787-3800Crossref PubMed Scopus (339) Google Scholar). Although PGRN has been shown to be involved in HCC progression, the functional role of PGRN in embryonic live organogenesis remains unknown. In the present study, we addressed two major issues. First, we assessed whether PGRN is involved in embryonic liver development. Second, we investigated the molecular mechanisms of PGRN in the regulation of liver growth. To study the genetic requirement of PGRN in embryonic liver development, we inhibited PGRN by antisense morpholino knockdown of the PGRN orthologue grnA in zebrafish. The Tg(fabp10:EGFP) model showed that GrnA knockdown led to a reduced liver size, which was verified using confocal imaging and immunohistochemistry (Fig. 2 and Table 1). This reduction suggests that GrnA is required for liver morphogenesis in zebrafish. An important issue is whether GrnA is specific for liver morphogenesis. PGRN is maternally deposited and then expressed zygotically in a number of epithelial cells, including the skin, the gastrointestinal tract, and immune cells (36Daniel R. Daniels E. He Z. Bateman A. Dev. Dyn. 2003; 227: 593-599Crossref PubMed Scopus (129) Google Scholar). In addition to the liver, our analysis revealed that GrnA affected the development of several tissues, including the pancreas and blood cells (Fig. 3 and data not shown). It is possible that grnA is widely expressed in many tissues in the zebrafish embryo (14Cadieux B. Chitramuthu B.P. Baranowski D. Bennett H.P. BMC Genomics. 2005; 6: 156Crossref PubMed Scopus (42) Google Scholar); therefore, its expression is required for the development of various tissues. However, during embryonic development, the liver is much more sensitive to a GrnA deficiency compared with other endoderm, mesoderm, and ectoderm-derived tissues (Fig. 3). This sensitivity indicates that GrnA plays a crucial role in liver organogenesis. Furthermore, we applied established WISH markers to frame the developmental stages that were affected by grnA knockdown and that led to impaired liver morphogenesis. At 24 hpf, the expression of hhex and prox1 led to normal liver bud formation, which suggested that specification was not disrupted in the grnA morphants. In contrast, our WISH results showed that hepatic outgrowth had been attenuated early with respect to the expression of ceruloplasmin from 40 hpf (data not shown) and foxA3 at 50 hpf (Fig. 7B). The expression of hhex, prox1, fabp10, foxA3, and cebpb in 72- and 96-hpf grnA morphants might have also led to the defective hepatic outgrowth observed in grnA morphants. Therefore, we conclude that GrnA is required for hepatic outgrowth rather than for specification in zebrafish. Numerous genes have been identified that are required for outgrowth, and it has been demonstrated that a loss of the expression of these genes decreases hepatic proliferation and leads to apoptosis (37Bonnard M. Mirtsos C. Suzuki S. Graham K. Huang J. Ng M. Itié A. Wakeham A. Shahinian A. Henzel W.J. Elia A.J. Shillinglaw W. Mak T.W. Cao Z. Yeh W.C. EMBO J. 2000; 19: 4976-4985Crossref PubMed Google Scholar, 38Rudolph D. Yeh W.C. Wakeham A. Rudolph B. Nallainathan D. Potter J. Elia A.J. Mak T.W. Genes Dev. 2000; 14: 854-862PubMed Google Scholar, 39Huang H. Ruan H. Aw M.Y. Hussain A. Guo L. Gao C. Qian F. Leung T. Song H. Kimelman D. Wen Z. Peng J. Development. 2008; 135: 3209-3218Crossref PubMed Scopus (69) Google Scholar, 40Sadler K.C. Krahn K.N. Gaur N.A. Ukomadu C. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 1570-1575Crossref PubMed Scopus (132) Google Scholar). PGRN has been reported to be a growth factor that stimulates cell proliferation (41He Z. Bateman A. Cancer Res. 1999; 59: 3222-3229PubMed Google Scholar, 42He Z. Ismail A. Kriazhev L. Sadvakassova G. Bateman A. Cancer Res. 2002; 62: 5590-5596PubMed Google Scholar) and decreases apoptosis (43Pizarro G.O. Zhou X.C. Koch A. Gharib M. Raval S. Bible K. Jones M.B. Int. J. Cancer. 2007; 120: 2339-2343Crossref PubMed Scopus (48) Google Scholar, 44Kim W.E. Serrero G. Clin. Cancer Res. 2006; 12: 4192-4199Crossref PubMed Scopus (34) Google Scholar, 45Tangkeangsirisin W. Hayashi J. Serrero G. Cancer Res. 2004; 64: 1737-1743Crossref PubMed Scopus (68) Google Scholar). The present work is the first to show that PGRN is involved in embryonic liver growth regulation. A loss of GrnA expression led to impaired proliferation and enhanced apoptosis in zebrafish embryos (Fig. 5 and supplemental Fig. S1). Similarly, the reduction of PGRN protein has been shown to suppress HCC proliferation in a nude mouse xenotransplantation model (10Cheung S.T. Wong S.Y. Leung K.L. Chen X. So S. Ng I.O. Fan S.T. Clin. Cancer Res. 2004; 10: 7629-7636Crossref PubMed Scopus (103) Google Scholar, 11Ho J.C. Ip Y.C. Cheung S.T. Lee Y.T. Chan K.F. Wong S.Y. Fan S.T. Hepatology. 2008; 47: 1524-1532Crossref PubMed Scopus (99) Google Scholar), which suggests a relevant regulatory mechanism of PGRN in HCC proliferation and embryonic liver growth. Besides, recent reports showed that the PGRN knock-out mice display behavioral abnormalities and dysregulated inflammation and neuropathology (46Kayasuga Y. Chiba S. Suzuki M. Kikusui T. Matsuwaki T. Yamanouchi K. Kotaki H. Horai R. Iwakura Y. Nishihara M. Behav. Brain Res. 2007; 185: 110-118Crossref PubMed Scopus (140) Google Scholar, 47Yin F. Banerjee R. Thomas B. Zhou P. Qian L. Jia T. Ma X. Ma Y. Iadecola C. Beal M.F. Nathan C. Ding A. J. Exp. Med. 2010; 207: 117-128Crossref PubMed Scopus (338) Google Scholar, 48Yin, F., Dumont, M., Banerjee, R., Ma, Y., Li, H., Lin, M. T., Beal, M. F., Nathan, C., Thomas, B., Ding, A. (2010) FASEB J., in press.Google Scholar). In contrast to our results shown in 4 dpf grnA knockdown zebrafish (Table 1), the ratio of liver weight over whole body weight is normal in the 2-month-old PGRN knock-out mice (47Yin F. Banerjee R. Thomas B. Zhou P. Qian L. Jia T. Ma X. Ma Y. Iadecola C. Beal M.F. Nathan C. Ding A. J. Exp. Med. 2010; 207: 117-128Crossref PubMed Scopus (338) Google Scholar). However, the detail examination remains to be seen whether the liver development is impaired in these animals. To elucidate the molecular mechanisms involved in GrnA-regulated liver growth, we performed a cDNA microarray analysis, which showed that GrnA modulated the expression of met and other related genes. During embryogenesis, Met and its ligand, the scatter factor/hepatocyte growth factor, play crucial roles in regulating liver development (49Schmidt C. Bladt F. Goedecke S. Brinkmann V. Zschiesche W. Sharpe M. Gherardi E. Birchmeier C. Nature. 1995; 373: 699-702Crossref PubMed Scopus (1222) Google Scholar), nerve outgrowth (50Maina F. Panté G. Helmbacher F. Andres R. Porthin A. Davies A.M. Ponzetto C. Klein R. Mol. Cell. 2001; 7: 1293-1306Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar), and myoblast migration from somites to the limbs (5Bladt F. Riethmacher D. Isenmann S. Aguzzi A. Birchmeier C. Nature. 1995; 376: 768-771Crossref PubMed Scopus (1087) Google Scholar, 35Latimer A.J. Jessen J.R. Dev. Dyn. 2008; 237: 3904-3915Crossref PubMed Scopus (17) Google Scholar). In addition, dysregulation of the MET signaling pathway promotes invasive growth and initiates metastasis during tumorigenesis (51Suzuki K. Hayashi N. Yamada Y. Yoshihara H. Miyamoto Y. Ito Y. Ito T. Katayama K. Sasaki Y. Ito A. et al.Hepatology. 1994; 20: 1231-1236Crossref PubMed Scopus (115) Google Scholar, 52Wang R. Ferrell L.D. Faouzi S. Maher J.J. Bishop J.M. J. Cell Biol. 2001; 153: 1023-1034Crossref PubMed Scopus (249) Google Scholar). The transcriptional induction of met has been determined in human HCC (53Ueki T. Fujimoto J. Suzuki T. Yamamoto H. Okamoto E. Hepatology. 1997; 25: 619-623Crossref PubMed Scopus (84) Google Scholar, 54Tavian D. De Petro G. Benetti A. Portolani N. Giulini S.M. Barlati S. Int. J. Cancer. 2000; 87: 644-649Crossref PubMed Scopus (97) Google Scholar), whereas little is known concerning its transcriptional regulation, except for the roles of ETS (55Gambarotta G. Boccaccio C. Giordano S. Andŏ M. Stella M.C. Comoglio P.M. Oncogene. 1996; 13: 1911-1917PubMed Google Scholar), hypoxia-inducible factor-1a (56Pennacchietti S. Michieli P. Galluzzo M. Mazzone M. Giordano S. Comoglio P.M. Cancer Cell. 2003; 3: 347-361Abstract Full Text Full Text PDF PubMed Scopus (1107) Google Scholar), yb1 (28Finkbeiner M.R. Astanehe A. To K. Fotovati A. Davies A.H. Zhao Y. Jiang H. Stratford A.L. Shadeo A. Boccaccio C. Comoglio P. Mertens P.R. Eirew P. Raouf A. Eaves C.J. Dunn S.E. Oncogene. 2009; 28: 1421-1431Crossref PubMed Scopus (72) Google Scholar), and β-catenin (57Boon E.M. van der Neut R. van de Wetering M. Clevers H. Pals S.T. Cancer Res. 2002; 62: 5126-5128PubMed Google Scholar). The met gene is a downstream target of β-catenin (57Boon E.M. van der Neut R. van de Wetering M. Clevers H. Pals S.T. Cancer Res. 2002; 62: 5126-5128PubMed Google Scholar), and MET is also known to induce β-catenin phosphorylation and accumulation (29Danilkovitch-Miagkova A. Miagkov A. Skeel A. Nakaigawa N. Zbar B. Leonard E.J. Mol. Cell. Biol. 2001; 21: 5857-5868Crossref PubMed Scopus (139) Google Scholar). In our model, GrnA-regulated mRNA expression of yb1, ctnnb1, and other MET related genes were confirmed using quantitative RT-PCR (Fig. 6A). GrnA also regulated met and β-catenin expression by Western blotting and WISH analyses (Fig. 8). Furthermore, β-catenin belongs to the Wnt signaling pathway and has been shown to regulate liver growth (58Apte U. Zeng G. Thompson M.D. Muller P. Micsenyi A. Cieply B. Kaestner K.H. Monga S.P. Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 292: G1578-G1585Crossref PubMed Scopus (96) Google Scholar), which suggests that Wnt signaling might also be of relevance and that extensive cellular pathways are affected by the knockdown of GrnA. Hence, it may explain why the met mRNA could not fully rescue the grnA morphant phenotype (Fig. 7, D and J). In rescue experiments, we found that a co-injection of met mRNA with grnA MO could restore the impaired liver growth caused by grnA MO administration; in contrast, grnA mRNA did not rescue the liver size resulting from the knockdown of MET (Fig. 7, F and L). Our results indicate that GrnA might serve as an upstream regulator of MET to regulate embryonic liver growth.Taken together, we demonstrate that zebrafish grnA is required for embryonic hepatic outgrowth, and that GrnA acts, at least partially, through MET signaling to regulate embryonic liver growth. Additionally, we provide a model that could be used to study both genetic and functional factors that are involved in embryonic liver morphogenesis. Because the PGRN receptor and downstream effectors have not yet been identified (59Lai A.Z. Abella J.V. Park M. Trends Cell Biol. 2009; 19: 542-551Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 60Xia X. Serrero G. Biochem. Biophys. Res. Commun. 1998; 245: 539-543Crossref PubMed Scopus (34) Google Scholar), our work proposes a possible crosstalk between PGRN and MET signaling and suggests new directions for future studies. IntroductionThe liver is the largest essential internal organ and has a number of vital functions in the body. The liver parenchyma is largely constituted of hepatocytes (∼80%), and the remaining cells include cholangiocytes, Kupffer cells, stellate cells, and sinusoidal endothelial cells (1Blouin A. Bolender R.P. Weibel E.R. J. Cell Biol. 1977; 72: 441-455Crossref PubMed Scopus (594) Google Scholar). Liver organogenesis is initiated in the endodermal cells of the ventral foregut, which develop competence from the cardiac mesoderm to form hepatoblasts. During the specification stages, the specified hepatoblasts form a liver bud and undergo the hepatic outgrowth process. Hepatic outgrowth is characterized by a large change in the liver bud size that is caused by the rapid proliferation of hepatoblasts. Finally, the hepatoblasts differentiate into functional hepatocytes and cholangiocytes (2Duncan S.A. Mech. Dev. 2003; 120: 19-33Crossref PubMed Scopus (145) Google Scholar, 3Zaret K.S. Nat. Rev. Genet. 2002; 3: 499-512Crossref PubMed Scopus (427) Google Scholar). In studies using chicks and mice, liver organogenesis has been shown to be tightly regulated by growth factors, cytokines, and transcription factors. However, little is known about the genetic requirements of the liver growth process and its regulatory mechanism. The use of knock-out mice has led to the discovery of several genes that are critical for hepatic outgrowth. An example of these critical genes is the met gene that encodes the hepatocyte growth factor receptor that regulates cell migration, proliferation, morphogenesis, and angiogenesis (4Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Nat. Rev. Mol. Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2209) Google Scholar). A knock-out of the met gene in mice results in early embryonic lethality and a reduced liver size in utero (5Bladt F. Riethmacher D. Isenmann S. Aguzzi A. Birchmeier C. Nature. 1995; 376: 768-771Crossref PubMed Scopus (1087) Google Scholar). In addition, growth hormone has been shown to be a liver growth-promoting factor (6Palmiter R.D. Norstedt G. Gelinas R.E. Hammer R.E. Brinster R.L. Science. 1983; 222: 809-814Crossref PubMed Scopus (480) Google Scholar). To investigate novel regulatory factors involved in liver growth, a subtractive hybridization in conjunction with growth hormone administration was performed. This hybridization led to the identification of progranulin (PGRN) 2The abbreviations used are: PGRNprogranulinHCChepatocellular carcinomahpfhours post-fertilizationMOmorpholinoWISHwhole-mount in situ hybridizationPH3phosphohistone H3PCNAproliferating cell nuclear antigendpfdays post-fertilizationEGFPenhanced green fluorescent protein. as a novel growth hormone-regulated growth factor in the liver (7Chen M.H. Li Y.H. Chang Y. Hu S.Y. Gong H.Y. Lin G.H. Chen T.T. Wu J.L. Gen. Comp. Endocrinol. 2007; 150: 212-218Crossref PubMed Scopus (22) Google Scholar).PGRN, also known as epithelin/granulin precursor, acrogranin, proepithelin, and PC cell-derived growth factor, is a pleiotropic autocrine growth factor that contributes to early embryogenesis, the wound healing response, frontotemporal dementia, and tumorigenesis (8He Z. Bateman A. J. Mol. Med. 2003; 81: 600-612Crossref PubMed Scopus (408) Google Scholar, 9Ong C.H. Bateman A. Histol. Histopathol. 2003; 18: 1275-1288PubMed Google Scholar). PGRN is an extracellular glycoprotein that consists of multiple copies of the cysteine-rich granulin motif. Elevated PGRN levels often occur in patients with cancer, and epidemiological studies show that PGRN is overexpressed in 70% of hepatocellular carcinoma (HCC) patients. Overexpression of PGRN promotes the growth and invasion of HCC cells (10Cheung S.T. Wong S.Y. Leung K.L. Chen X. So S. Ng I.O. Fan S.T. Clin. Cancer Res. 2004; 10: 7629-7636Crossref PubMed Scopus (103) Google Scholar). Treatment with a PGRN monoclonal antibody has been shown to block the established HCC tumor growth in a mouse xenotransplantation model (11Ho J.C. Ip Y.C. Cheung S.T. Lee Y.T. Chan K.F. Wong S.Y. Fan S.T. Hepatology. 2008; 47: 1524-1532Crossref PubMed Scopus (99) Google Scholar), which suggests that PGRN is involved in regulating pathological hepatocyte growth. Although the dysregulation of embryonic hepatogenesis signaling has been shown to be associated with hepatocarcinogenesis (12Breuhahn K. Longerich T. Schirmacher P. Oncogene. 2006; 25: 3787-3800Crossref PubMed Scopus (339) Google Scholar), the physiological role of PGRN in hepatogenesis remains unclear.Zebrafish are an ideal model for studying the physiological role of PGRN in hepatogenesis because early stages of liver organogenesis in zebrafish are similar to those observed in mice (13Chu J. Sadler K.C. Hepatology. 2009; 50: 1656-1663Crossref PubMed Scopus (146) Google Scholar). There are four PGRN genes (grnA, grnB, grn1, and grn2) in the zebrafish genome, whereas only one gene encodes PGRN in mammals. According to the syntenic conservation of chromosomal localization, grnA is the orthologue of the mammalian PGRN gene. In zebrafish, the expression of grnA has been observed in the anterior endoderm and the liver primordium from 24 to 120 h post-fertilization (hpf) (14Cadieux B. Chitramuthu B.P. Baranowski D. Bennett H.P. BMC Genomics. 2005; 6: 156Crossref PubMed Scopus (42) Google Scholar), which suggests that grnA might contribute to liver development. In the present study, we knocked down GrnA expression using morpholinos (MOs), which resulted in a small liver phenotype in zebrafish. According to the whole-mount in situ hybridization (WISH) analysis, we determined that the morphological defect was caused by an impaired hepatic outgrowth. Furthermore, a microarray approach combined with in vitro and in vivo examinations revealed that GrnA was an upstream factor of MET signaling in liver growth. Taken together, our findings indicate that GrnA is essential for embryonic liver morphogenesis. In addition, our findings also indicate a possible relationship between PGRN and MET signaling." @default.
• W2051570658 created "2016-06-24" @default.
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• W2051570658 date "2010-12-01" @default.
• W2051570658 modified "2023-10-17" @default.
• W2051570658 title "Progranulin A-mediated MET Signaling Is Essential for Liver Morphogenesis in Zebrafish" @default.
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