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Published on: February 2, 2018
Hepatomegaly in transgenic mice expressing the homeobox gene Cux-1
Gregory B Vanden Heuvel1, Jennifer G Brantley, Neal I Alcalay
1Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, 66160, USA.
Abstract:
Cux-1 is a member of a family of homeobox genes structurally related to Drosophila Cut. Mammalian Cut proteins function as transcriptional repressors of genes specifying terminal differentiation in multiple cell lineages. In addition, mammalian Cut proteins serve as cell-cycle-dependent transcriptional factors in proliferating cells, where they function to repress expression of the cyclin kinase inhibitors p21 and p27. Previously we showed that transgenic mice expressing Cux-1 under control of the CMV immediate early gene promoter develop multiorgan hyperplasia. Here we show that mice constitutively expressing Cux-1 exhibit hepatomegaly correlating with an increase in cell proliferation. In addition, the increase in Cux-1 expression in transgenic livers was associated with a decrease in p21, but not p27, expression. Within transgenic livers, Cux-1 was ectopically expressed in a population of small cells, but not in mature hepatocytes, and many of these small cells expressed markers of proliferation. Transgenic livers showed an increase in alpha-smooth muscle actin, indicating activation of hepatic stellate cells, and an increase in cells expressing chromogranin-A, a marker for hepatocyte precursor cells. Morphological analysis of transgenic livers revealed inflammation, hepatocyte swelling, mixed cell foci, and biliary cell hyperplasia. These results suggest that increased expression of Cux-1 may play a role in the activation of hepatic stem cells, possibly through the repression of the cyclin kinase inhibitor p21.
Insights
Increased Cux-1 expression in mice causes liver enlargement and promotes cell proliferation by repressing the cyclin kinase inhibitor p21, suggesting a role in hepatic stem cell activation.
Area of Science:
- Molecular Biology
- Developmental Biology
- Hepatology
Background:
- Cux-1 is a homeobox gene regulating cell differentiation and proliferation.
- Mammalian Cut proteins act as transcriptional repressors, including for cell cycle inhibitors p21 and p27.
- Previous studies showed Cux-1 overexpression leads to multiorgan hyperplasia.
Purpose of the Study:
- To investigate the role of Cux-1 in liver biology, specifically its effects on cell proliferation and differentiation.
- To determine the impact of constitutive Cux-1 expression on liver morphology and cellular markers.
Main Methods:
- Generation of transgenic mice with constitutive Cux-1 expression.
- Analysis of liver morphology, cell proliferation markers, and expression of p21 and p27.
- Immunohistochemical analysis for markers of hepatic stellate cells (alpha-smooth muscle actin) and hepatocyte precursors (chromogranin-A).
Main Results:
- Constitutive Cux-1 expression resulted in hepatomegaly and increased liver cell proliferation.
- Cux-1 overexpression led to decreased p21 expression but not p27.
- Ectopic Cux-1 expression was observed in proliferating small cells, not mature hepatocytes, with increased markers for hepatic stellate cells and hepatocyte precursors.
- Morphological changes included inflammation, hepatocyte swelling, and biliary cell hyperplasia.
Conclusions:
- Increased Cux-1 expression promotes liver cell proliferation and potentially activates hepatic stem cells.
- Repression of p21 by Cux-1 may be a key mechanism in this process.
- Cux-1 plays a significant role in regulating liver cell growth and differentiation pathways.
