THE LIVER IN TRANSFORMING GROWTH-FACTOR-BETA-1 (TGF-BETA-1) NULL MUTANT MICE

Transforming growth factor-beta-1 (TGF-beta 1) null mutant mice have n o gross developmental abnormalities at birth but succumb to multifocal inflammatory lesions that lead to organ failure and death about 20 da ys after birth. Treatment with anti-inflammatory and immune suppressiv e agents, such as rapamycin, reduces the severity and extent of inflam matory infiltrates in the liver and can prolong the life of knockout ( KO) mice compared to untreated null mice. To determine whether there i s an associated hepatic phenotype, livers of ''young'' (<3 weeks), ''o ld'' (>3 weeks), and age-matched wild-type (WT) mice were studied usin g light and electronmicroscopy. On light microscopy, old KO mice had f oci of mononuclear cells in liver parenchyma in addition to scattered foci of megalocytosis. Intracytoplasmic vacuoles, some of which were j uxtanuclear in location, were also seen but these were most prominent in the oldest (10 weeks) rapamycin-treated mouse. In the untreated you ng KO mice, there were only foci of mononuclear cells in the liver par enchyma and portal tracts and variable numbers of binucleated hepatocy tes. 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). Hepatoc ytes from all KO mice showed increased numbers of hypertrophied or enl arged Golgi complexes compared to age-matched wild-type mice. Intracyt oplasmic canaliculi lined with microvilli were seen in livers of old K O mice, but were absent in the young KO and wild-type mice. Primary cu ltures of hepatocytes, derived from livers of both young and old KO mi ce, showed similar changes on phase contrast and electronmicroscopy. T hese included juxtanuclear vacuoles, intracytoplasmic canaliculi, enla rged Golgi vesicles, and increased numbers of autolysosomes. Phenotypi c abnormalities of mitochondria were either minimal or absent in cultu red KO hepatocytes. The findings demonstrate, for the first time, that targeted disruption of the TGF-beta 1 gene in mice results in an alte red ultrastructural phenotype of hepatocytes. The data suggest that TG F-beta 1 may be required for normal development and regulation of subc ellular organelles in hepatocytes and may be essential for physiologic al functions involving mitochondria and Golgi complex.