Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U.Leuven, B-3000 Leuven, Belgium.
Mol Genet Metab. 2010 May;100(1):71-6. doi: 10.1016/j.ymgme.2010.02.003. Epub 2010 Feb 12.
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.
导致严重过氧化物酶体生物发生障碍患者和小鼠皮质神经元迁移缺陷、张力减退和小脑畸形的代谢因素仍未确定。在本研究中，我们检验了这样一个假设，即过氧化物酶体β-氧化和醚脂生物合成的联合失活可能是这些病理的根源。生成了双 MFP2/DAPAT 敲除小鼠，并比较了它们与单敲除和对照小鼠的出生后表型。DAPAT 敲除小鼠的皮质神经元迁移不受影响，而双 MFP2/DAPAT 敲除小鼠的影响则较为轻微。后者小鼠严重张力减退，通常在出生后死亡。DAPAT 和 MFP2 单敲除小鼠的小脑叶片形成均出现延迟。我们得出结论，过氧化物酶体β-氧化和醚脂合成的联合缺陷并不能完全解释过氧化物酶体生物发生障碍小鼠的典型皮质神经元迁移缺陷，而是导致它们张力减退的原因之一。
