Related Experiment Videos
The liver in transforming growth factor-Beta-1 (TGF-beta 1) null mutant mice
A O Williams1, A D Knapton, A Geiser
1Laboratory of Experimental Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA.
Abstract:
Transforming growth factor-beta-1 (TGF-beta 1) null mutant mice have no gross developmental abnormalities at birth but succumb to multifocal inflammatory lesions that lead to organ failure and death about 20 days after birth. Treatment with anti-inflammatory and immune suppressive agents, such as rapamycin, reduces the severity and extent of inflammatory infiltrates in the liver and can prolong the life of knockout (KO) mice compared to untreated null mice. To determine whether there is an associated hepatic phenotype, livers of "young" (< 3 weeks), "old" (> 3 weeks), and age-matched wild-type (WT) mice were studied using light and electronmicroscopy. On light microscopy, old KO mice had foci of mononuclear cells in liver parenchyma in addition to scattered foci of megalocytosis. Intracytoplasmic vacuoles, some of which were juxtanuclear in location, were also seen but these were most prominent in the oldest (10 weeks) rapamycin-treated mouse. In the untreated young KO mice, there were only foci of mononuclear cells in the liver parenchyma and portal tracts and variable numbers of binucleated hepatocytes. Ultrastructurally, there was a significant increase in the number of mitochondria in livers of the old KO mice, when compared either to the age-matched wild-type or to the young KO mice (p > .001). Hepatocytes from all KO mice showed increased numbers of hypertrophied or enlarged Golgi complexes compared to age-matched wild-type mice. Intracytoplasmic canaliculi lined with microvilli were seen in livers of old KO mice, but were absent in the young KO and wild-type mice. Primary cultures of hepatocytes, derived from livers of both young and old KO mice, showed similar changes on phase contrast and electronmicroscopy. These included juxtanuclear vacuoles, intracytoplasmic canaliculi, enlarged Golgi vesicles, and increased numbers of autolysosomes. Phenotypic abnormalities of mitochondria were either minimal or absent in cultured KO hepatocytes. The findings demonstrate, for the first time, that targeted disruption of the TGF-beta 1 gene in mice results in an altered ultrastructural phenotype of hepatocytes. The data suggest that TGF-beta 1 may be required for normal development and regulation of subcellular organelles in hepatocytes and may be essential for physiological functions involving mitochondria and Golgi complex.
Insights
Transforming growth factor-beta-1 (TGF-beta 1) null mutant mice exhibit liver cell abnormalities, including mitochondrial and Golgi complex changes. These findings reveal TGF-beta 1
Area of Science:
- Hepatology and Molecular Biology
- Cellular Ultrastructure and Organelle Biology
- Immunology and Inflammation
Background:
- Transforming growth factor-beta-1 (TGF-beta 1) null mutant mice develop fatal inflammatory lesions by 3 weeks of age.
- Rapamycin treatment can mitigate inflammation and prolong survival in these mice.
- The hepatic phenotype and cellular changes in TGF-beta 1 deficient mice remain largely uncharacterized.
Purpose of the Study:
- To investigate the hepatic phenotype in TGF-beta 1 null mutant mice.
- To characterize the ultrastructural changes in hepatocytes of these mice.
- To determine the role of TGF-beta 1 in hepatocyte development and organelle regulation.
Main Methods:
- Light and electron microscopy of liver tissues from young and old TGF-beta 1 knockout (KO) and wild-type (WT) mice.
- Histological analysis of inflammatory infiltrates and cellular morphology.
- Ultrastructural examination of mitochondria, Golgi complexes, and other organelles.
- Primary culture of KO hepatocytes for detailed ultrastructural analysis.
Main Results:
- Old KO mice displayed mononuclear cell foci, megalocytosis, and increased mitochondria compared to WT mice.
- Hepatocytes from all KO mice showed enlarged Golgi complexes and increased autolysosomes.
- Intracytoplasmic canaliculi were observed in old KO mice but not in young KO or WT mice.
- Cultured KO hepatocytes exhibited similar ultrastructural changes, with minimal mitochondrial abnormalities.
Conclusions:
- Targeted disruption of the TGF-beta 1 gene induces a distinct ultrastructural hepatocyte phenotype.
- TGF-beta 1 is crucial for the normal development and regulation of subcellular organelles in hepatocytes.
- The study highlights the essential role of TGF-beta 1 in maintaining hepatocyte structure and function, particularly involving mitochondria and Golgi complexes.