Open AccessGenetic disruption of Pten in a novel mouse model of tomaculous neuropathy
Author(s) -
Goebbels Sandra,
Oltrogge Jan H.,
Wolfer Susanne,
Wieser Georg L.,
Nientiedt Tobias,
Pieper Alexander,
Ruhwedel Torben,
Groszer Matthias,
Sereda Michael W.,
Nave KlausArmin
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200227
Subject(s) - pten , myelin , pi3k/akt/mtor pathway , protein kinase b , neuregulin , neuregulin 1 , mapk/erk pathway , kinase , neuroscience , microbiology and biotechnology , cancer research , biology , hyperactivation , pathology , signal transduction , medicine , central nervous system
‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin‐1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P 3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non‐compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.