Transcriptional control in hepatocytes of normal and c14CoS albino deletion mice.

Abstract

The transcription rates of the albumin and alpha‐fetoprotein (alpha FP) genes were reduced to marginally detectable levels in livers of newborn or fetal c14CoS albino deletion mutant mice, which lack the hepatocyte specific developmental regulation (hsdr‐1) locus on chromosome 7 and die shortly after birth. However, steady‐state levels of these two mRNAs in livers of mutant mice were similar to those in normal mice, where these genes are actively transcribed. In c14CoS mice, transcription rates of transcription factor genes HNF‐1, C/EBP and HNF‐4 were reduced, albeit to different extents. These effects are specific because transcription of the HNF‐3, DBP, LAP and Jun‐B genes remained normal in mutant mice. Steady‐state levels of all of these mRNAs reflected the transcriptional activities. Levels of HNF‐1 and HNF‐4 mRNAs showed much greater depression than that of C/EBP in mutant liver. The availability of this group of transcription factors may be reduced in c14CoS hepatocytes and therefore caused depressed transcription rates of their target genes such as those encoding albumin and alpha FP. However, the normal steady‐state levels of albumin and alpha FP mRNAs in mutant mice remains unexplained. Fetal c14CoS hepatocytes in primary culture did acquire competence for glucocorticoid inducible transcription of the albumin, alpha FP, HNF‐4 and metallothionein genes but not of the tyrosine aminotransferase (TAT) gene. These results indicate that the hsdr‐1 locus is dispensable for the glucocorticoid induced transcription of these genes but not of TAT. The effects caused by the c14CoS deletion are pleiotropic in controlling the expression of numerous genes at distinct levels in the liver.

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

“…Sudden apoptotic death of unmasked phenotype of HT1 in mature and unmodified hepatocytes had not been expected (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)16), and these are implications for the pathogenesis and treatment of liver disease in HT1 patients. We suggest that mature and unmodified hepatocytes in those with the FAH defect cannot survive and that hepatocytes in the chronic form of HT1 have to be protected from a likely acute death.…”

“…Lethal albino deletion c 14CoS mice and mice with targetdisrupted Fah are models for HT1 (5)(6)(7)(8)(9)(10)(11)(12), but these mice die in the perinatal period, bearing a phenotype different from that seen in HT1 patients (5)(6)(7)(8)(9). Studies on these mice revealed impairment of expression of developmentally regulated genes that are essential for liver functions (6 -11).…”

Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1.

“…The locus has been named hsdr-1 (hepatocyte-specific developmental regulation-l; McKnight et al 1989) and alf (albino lethal mutation factor; Ruppert et al 1990), and is referred to here as alf/hsdr-1. Subsequent findings that the genes for several liver-enriched transcription factors are also down-regulated (McKnight et al 1989;Gonzalez et al 1990;Ruppert et al 1990;T6njes et al 1992) have implied a more widespread effect on gene expression than recognized previously. It may be anticipated that a deficit of such factors will impair the induction of hormone-responsive genes.…”

Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice.

“…The first might involve reduced expression of transcription factors: The mRNAs for hepatic nuclear factors HNF-1 and HNF-4 are affected most strongly T6njes et al 1992), while HNF-3 and C/EBP show modest reductions (McKnight et al 1989;Ruppert et al 1990;T6njes et al 1992). One or more of these factors might be required for hormone-dependent and/or high-level expression of the TAT and PEPCK genes.…”

“…A specific deficit of factors in the signal transduction pathways for glucocorticoid and cAMP has not been found, however DeFranco et al 1991). In contrast, the mRNAs for some transcription factors enriched in liver, C/EBP, HNF-1, and HNF-4, are present at reduced levels (McKnight et al 1989;Gonzalez et al 1990;Ruppert et al 1990;T6njes et al 1992).…”