Development of the mammalian liver requires the rapid proliferation of hepatoblasts that is an integral feature of hepatogenesis. This proliferation is dependent upon the action of specific mitogens, such as hepatocyte growth factor, and mutations that affect hepatic mitogenic signaling pathways result in hypoplasia of the fetal liver. Not surprisingly, these factors are also important regulators of liver regeneration and have been implicated in progression of hepatocellular carcinomas. For these reasons the action of hepatic mitogens, and the signal transduction pathways they activate, have been studied intensely. One consequence of mitogenic stimulation is the onset of expression of immediate and delayed response genes that have important roles in controlling cell cycle progression. Most of these factors are expressed in all cell types and, therefore, do not specifically regulate hepatocyte proliferation. However, disruption of the pescadillo gene in zebrafish dramatically arrests fetal hepatoblast proliferation without affecting growth of the entire embryo. This implies that specific mechanisms exist to control proliferation of fetal liver cells during embryonic development. We have identified the mouse homolog of pescadillo, Pes1, and shown that it encodes a nuclear protein containing a BRCT domain. BRCT domains define a superfamily of proteins, including the breast cancer susceptibility protein BRCA1, which have diverse roles in cell proliferation. Based on our preliminary studies and the phenotype of pescadillo-deficient zebrafish embryos, we hypothesize that Pes1 protein specifically regulates proliferation of hepatic cells during development by controlling the action or expression of proteins involved in cell cycle progression. We, therefore, propose to test this hypothesis by i) determining the physical and biochemical properties of Pes1 protein that are important for its function, ii) elucidating the molecular pathways that utilize Pes1 function by identifying Pes1 binding partners, and iii) examining the physiological role of Pes1 during embryogenesis using Pes1 """"""""knockout"""""""" mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK060064-01
Application #
6365089
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Serrano, Jose
Project Start
2001-09-21
Project End
2005-07-31
Budget Start
2001-09-21
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$276,250
Indirect Cost
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Zhao, Roong; Watt, Alistair J; Li, Jixuan et al. (2005) GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol 25:2622-31
Gupta, Rana K; Vatamaniuk, Marko Z; Lee, Catherine S et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115:1006-15
Lazarevich, Natalia L; Cheremnova, Oksana A; Varga, Ekaterina V et al. (2004) Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology 39:1038-47
Watt, Alistair J; Battle, Michele A; Li, Jixuan et al. (2004) GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci U S A 101:12573-8
Duncan, Stephen A (2003) Mechanisms controlling early development of the liver. Mech Dev 120:19-33
Watt, Alistair J; Garrison, Wendy D; Duncan, Stephen A (2003) HNF4: a central regulator of hepatocyte differentiation and function. Hepatology 37:1249-53
Misra, Ravi P; Duncan, Stephen A (2002) Gene targeting in the mouse: advances in introduction of transgenes into the genome by homologous recombination. Endocrine 19:229-38
Parviz, Fereshteh; Li, Jixuan; Kaestner, Klaus H et al. (2002) Generation of a conditionally null allele of hnf4alpha. Genesis 32:130-3
Lerch-Gaggl, Alexandra; Haque, Jamil; Li, Jixuan et al. (2002) Pescadillo is essential for nucleolar assembly, ribosome biogenesis, and mammalian cell proliferation. J Biol Chem 277:45347-55
Misra, R P; Bronson, S K; Xiao, Q et al. (2001) Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation. BMC Biotechnol 1:12