Combined deficiency of peroxisomal beta-oxidation and ether lipid synthesis in mice causes only minor cortical neuronal migration defects but severe hypotonia.
The metabolic factors causing cortical neuronal migration defects, hypotonia and malformation of cerebellum in patients and mice with severe peroxisome biogenesis disorders are still not identified. In the present investigation, we tested the hypothesis that the combined inactivity of peroxisomal beta-oxidation and ether lipid biosynthesis could be at the origin of these pathologies. Double MFP2/DAPAT knockout mice were generated and their postnatal phenotypes were compared with single knockouts and control mice. Cortical neuronal migration was not affected in DAPAT knockouts and only mildly in double MFP2/DAPAT knockout mice. The latter mice were severely hypotonic and usually died in the postnatal period. Both DAPAT and MFP2 single knockout mice exhibited delays in the formation of cerebellar folia. We conclude that the combined defect of peroxisomal beta-oxidation and ether lipid synthesis does not solely account for the typical cortical neuronal migration defect of mice with peroxisome biogenesis disorders but contributes to their hypotonia.
Krysko
Olga
O
Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U.Leuven, B-3000 Leuven, Belgium.
Bottelbergs
Astrid
A
Van Veldhoven
Paul
P
Baes
Myriam
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics*; D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002531:Cerebellum / Q000254:growth & development; D002540:Cerebral Cortex / Q000378:metabolism; D004746:Enoyl-CoA Hydratase / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000502:physiology*
D009097:Multienzyme Complexes; D015067:17-Hydroxysteroid Dehydrogenases; C491288:Hsd17b4 protein, mouse; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase; D064029:Peroxisomal Multifunctional Protein-2; D004746:Enoyl-CoA Hydratase