Human Molecular Genetics Advance Access published online on March 8, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp110
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum
1 University of Heidelberg, Heidelberg Center of Biochemistry (BZH) 2 Department of Anatomy and Cell Biology, University of Heidelberg 3 Department of Physiology, University of Heidelberg
* Corresponding author: Dr. Wilhelm W. Just, University of Heidelberg, Heidelberg Center of Biochemistry (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Tel.: ++49 6221 544151, Fax.: ++49 6221 544366 e-mail: Wilhelm.just{at}bzh.uni-heidelberg.de
Received December 29, 2008; Revised February 22, 2009; Accepted March 5, 2009
Ether lipids (ELs), particularly plasmalogens, are essential constituents of the mammalian central nervous system. The physiological role of ELs, in vivo, however is still enigmatic. In the present study we characterized a mouse model carrying a targeted deletion of the peroxisomal dihydroxyacetonephosphate acyltransferase (DAPAT) gene that results in the complete lack of ELs. Investigating the cerebellum of these mice, we observed: (i) defects in foliation patterning and delay in precursor granule cell migration, (ii) defects in myelination and concomitant reduction in the level of myelin basic protein, (iii) disturbances in paranode organization by extending the Caspr distribution and disrupting axo-glial septate-like junctions, (iv) impaired innervation of Purkinje cells (PCs) by both parallel fibers and climbing fibers (v) and formation of axon swellings by the accumulation of inositol-tris-phosphate receptor 1-containing smooth ER-like tubuli. Functionally, conduction velocity of myelinated axons in the corpus callosum was significantly reduced. Most of these phenotypes were already apparent at P20 but still persisted in one-year-old animals. In summary, these data show that EL deficiency results in severe developmental and lasting structural alterations at the cellular and network level of the cerebellum, and reveal an important role of ELs for proper brain function. Common molecular mechanisms that may underlie these phenotypes are discussed.
4 Present address: Division of Medical Physics in Radiology, German Cancer Research Center, Heidelberg