The growth retardation and liver dysfunction of PERK knockout mice

Open Access
- Author:
- LI, YULIN
- Graduate Program:
- Genetics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 20, 2006
- Committee Members:
- Douglas Cavener, Committee Member
Gong Chen, Committee Member
Bernhard Luscher, Committee Chair/Co-Chair
Richard W Ordway, Committee Member
Robert Paulson, Committee Member - Keywords:
- PERK
Liver dysfunction
Steatosis
Wolcott-Rallison syndrome
growth retardation
EIF2AK3 - Abstract:
- Mutations of PKR-like Endoplasmic Reticulum Kinase (PERK) eIF2alpha kinase cause multiple phenotypes in both human and mice. Perk mutations in human result in Wolcott- Rallison syndrome. The human patients had neonatal diabetes, osteoporosis and growth retardation. However, according to clinical observations, most of the Wolcott-Rallison syndrome patients also had recurrent liver dysfunction/failure and they died from liver dysfunction instead of diabetes and osteoporosis. I used the Perk-/- mice to study the growth retardation of the mice and found out that Insulin-Like Growth Factor I (IGF-I) was closely correlated with the body weight of both wild type and knockout mice. The serum IGF-I reduction in Perk-/- mice was due to reduced IGF-I mRNA level in liver. Injection of recombinant IGF-I in neonatal Perk-/- mice partially rescued their growth retardation, suggesting that the IGF-I was important for their growth retardation. The IGF-I changes were also correlated with the development of liver dysfunction in Perk-/- mice. In the neonatal Perk-/- mouse liver, where the dramatic reduction of IGF-I level was found, I also observed severe fat accumulation, increased glycogen storage and other mild pathological changes. I further tested whether this liver dysfunction was a hepatocyte cell autonomous defect using both liver specific Perk conditional knockout mouse models and liver specific Perk transgenic mouse model. With the liver specific Cre expression, I was able to obtain considerable Perk gene deletion in neonatal mouse liver, but no phenotype was observed. In addition to the liver specific conditional knockout mice models, I also constructed a liver specific Perk transgenic mouse model and was able to confirm the expression of functional Perk in the mice but it failed to rescue the growth retardation and liver dysfunction in the global Perk-/- mice. Taken together, these results suggest that the growth retardation and liver dysfunction in the Perk-/- mice may not be a cell autonomous defect of hepatocytes. Moreover, our data suggest that the Perk-/- liver dysfunction closely resembles the metabolic syndrome seen in protein energy malnutrition.