Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice

Abstract

Although known for almost 80 years, the physiological role of plasmalogens (PLs), the major mammalian ether lipids (ELs), is still enigmatic. Humans that lack ELs suffer from rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder usually resulting in death in early childhood. In order to learn more about the functions of ELs, we generated a mouse model for RCDP by a targeted disruption of the dihydroxyacetonephosphate acyltransferase gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract and optic nerve hypoplasia, some of which were also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain PLs and the occurrence of PLs in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, PLs were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 and F3/contactin were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin 43, known to be recruited to LRMs and essential for lens development and spermatogenesis, was down-regulated in embryonic fibroblasts of the EL-deficient mice. Free cholesterol, an important constituent of LRMs, was found in these fibroblasts to be accumulated in a perinuclear compartment. These data suggest that the EL-deficient mice allow the identification of new phenotypes not related so far to EL-deficiency (male sterility, defects in myelination and optic nerve hypoplasia) and indicate that PLs are required for the correct assembly and function of LRMs.

Role of dihydroxyacetonephosphate acyltransferase in the biosynthesis of plasmalogens and nonether glycerolipids

“…This is in agreement with evidence presented by Ofman, Lajmir, and Wanders (38) and Rodemer et al (39). The evidence presented here also argues against this activity as a controlling factor in plasmalogen biosynthesis.…”

The neurology of rhizomelic chondrodysplasia punctata

“…, but is normal in the Pex7 neo/neo mice [18][19][20][21]. Epilepsy has not been mentioned in the mice.…”

Absence of Functional Peroxisomes from Mouse CNS Causes Dysmyelination and Axon Degeneration

“…Because the precise role of ether, as opposed to esterphospholipids, is an unresolved issue, the consequence of this switch for the formation and maintenance of myelin remains hypothetical. Ether-bonded lipids might have a double role in lipid raft microdomains because, on the one hand, plasmenylethanolamines are enriched in these domains (Pike et Rodemer et al, 2003), and, in addition, many GPI anchored proteins contain a 1-alkyl-2-acyl-glycerol moiety in their lipid anchor (Gorgas et al, 2006). This is relevant for the organization of myelin because several myelin proteins like PLP, CNP, and oligodendrocyte-myelin glycoprotein are enriched in lipid rafts (DeBruin and Harauz, 2007).…”