P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves.
We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.
Wrabetz
L
L
Department of Neurology and Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, 20132 Milano, Italy. l.wrabetz@hsr.it
Feltri
M L
ML
Quattrini
A
A
Imperiale
D
D
Previtali
S
S
D'Antonio
M
M
Martini
R
R
Yin
X
X
Trapp
B D
BD
Zhou
L
L
Chiu
S Y
SY
Messing
A
A
D000818:Animals; D015153:Blotting, Western; D003711:Demyelinating Diseases / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics; D018993:Myelin P0 Protein / Q000096:biosynthesis* / Q000235:genetics*; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D010523:Peripheral Nervous System Diseases / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000378:metabolism / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism / Q000648:ultrastructure
D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger