ABSTRACT
Human peroxisome biogenesis disorders are lethal genetic diseases in which abnormal peroxisome assembly compromises overall peroxisome and cellular function. Peroxisomes are ubiquitous membrane-bound organelles involved in several important biochemical processes, notably lipid metabolism and the use of reactive oxygen species for detoxification. Using cultured cells, we systematically characterized the peroxisome assembly phenotypes associated with dsRNA-mediated knockdown of 14 predicted Drosophila homologs of PEX genes (encoding peroxins; required for peroxisome assembly and linked to peroxisome biogenesis disorders), and confirmed that at least 13 of them are required for normal peroxisome assembly. We also demonstrate the relevance of Drosophila as a genetic model for the early developmental defects associated with the human peroxisome biogenesis disorders. Mutation of the PEX1 gene is the most common cause of peroxisome biogenesis disorders and is one of the causes of the most severe form of the disease, Zellweger syndrome. Inherited mutations in Drosophila Pex1 correlate with reproducible defects during early development. Notably, Pex1 mutant larvae exhibit abnormalities that are analogous to those exhibited by Zellweger syndrome patients, including developmental delay, poor feeding, severe structural abnormalities in the peripheral and central nervous systems, and early death. Finally, microarray analysis defined several clusters of genes whose expression varied significantly between wild-type and mutant larvae, implicating peroxisomal function in neuronal development, innate immunity, lipid and protein metabolism, gamete formation, and meiosis.
Subject(s)
Disease Models, Animal , Drosophila melanogaster/metabolism , Peroxisomal Disorders/pathology , Zellweger Syndrome/pathology , Animals , Conserved Sequence/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/embryology , Drosophila melanogaster/genetics , Embryo, Nonmammalian/metabolism , Embryo, Nonmammalian/pathology , Gene Expression Regulation, Developmental , Genes, Insect , Homozygote , Larva/metabolism , Membrane Proteins/metabolism , Mutation/genetics , Neuroglia/metabolism , Neuroglia/pathology , Neurons/metabolism , Neurons/pathology , Organ Specificity , Peroxisomal Disorders/genetics , Peroxisomes/metabolism , RNA Interference , RNA, Double-Stranded/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , Sequence Homology, Amino Acid , Zellweger Syndrome/geneticsABSTRACT
A number of studies have suggested the incompatibility of simultaneous increases in immune and reproductive functions. Other research has indicated that immune responses may be modulated depending on the relative benefits of increased survival and prospects for current and future reproduction. We tested the hypothesis that energy allocation to reproductive and other organ systems is not affected by testosterone level and energy expenditure on immune functions. Adult male white-footed mice (Peromyscus leucopus) with or without elevated testosterone levels and with or without immunochallenges were tested. Testosterone treatment was associated with reduced humoral immune response indicating immunosuppressive effects, reduced masses of gastrointestinal organs, reduced corticosterone level, increased kidney and seminal vesicle masses, and increased hematocrit. Immunochallenge was associated with increased resting metabolic rate and testes and seminal vesicle masses. Reproductive organ masses were greatest in immunochallenged mice with exogenous testosterone. Simultaneous increases in energy allocation to immune and reproductive structures may be an adaptive response that would enhance survival and current prospects for reproduction.
