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32 The role of vertebrate neurogenic genes in early neurogenesis
Author(s) -
Chitnis A.,
Kinuier C.
Publication year - 1996
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/0736-5748(96)80227-9
Subject(s) - neurogenesis , citation , library science , vertebrate , world wide web , biology , neuroscience , computer science , gene , genetics
Myelination requites the coordinate expression of genes which encode integral membrane proteins of the myelin sheath Proteins such as PLP/DMM in oligodendrocytes, or PMP22 in Schwann cells, belong to a diverse group of 4-helix span membrane proteins. Although they are ‘myelin proteins’ and thought to contribute to the architecture of the compacted myelin sheath, their specific cellular function is still unknown. The genes encoding PLP and PMP22 have been associated with inherited neurological diseases in mouse and man, caused by point mutations and gene duplications (Pelizaeus-Menbacher disease; Chorcot-Marie-Tooth disease). To better understand the PLP-dependent disease mechanism, we have generated PLP uansgenic (“overexpressing”) and PLP “knock-out” mice and compared these models to known mutant allels (iimpy, rumpshaker) carrying PLP point mutations. Our studies support the concept that the more severe pathological changes found in the natural mutants and the human disease result hugely from abnormal “gain of function” effects of misfolded PLP, rather than from a primary defect in the myelin architecture. Some of the in viva observations have been complemented in vitro: overexpression of mutant or wildtype PLP/DM20 in transfected fibrobIasts allows to monitor the subcellular distribution of these membrane proteins and reveals that mutant forms are recognized as such by heterologous cells and retained in the ER. Colocalization of epitope-tagged and wildtype PLP provides indirect evidence for oligomeriration of this myelin protein (Supported by a grant from the DFG, SFB 3 17).