title: Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy.
abstract: '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.
authors.affiliation: Max-Planck-Institute of Experimental Medicine, Göttingen, Germany. sgoebbels@em.mpg.de
authors.forename: Sandra
authors.initials: S
authors.lastname: Goebbels
authors.forename: Jan H
authors.initials: JH
authors.lastname: Oltrogge
authors.forename: Susanne
authors.initials: S
authors.lastname: Wolfer
authors.forename: Georg L
authors.initials: GL
authors.lastname: Wieser
authors.forename: Tobias
authors.initials: T
authors.lastname: Nientiedt
authors.forename: Alexander
authors.initials: A
authors.lastname: Pieper
authors.forename: Torben
authors.initials: T
authors.lastname: Ruhwedel
authors.forename: Matthias
authors.initials: M
authors.lastname: Groszer
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
mesh_terms: D000818:Animals; D001176:Arthrogryposis / Q000473:pathology*; D002460:Cell Line; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D015417:Hereditary Sensory and Motor Neuropathy / Q000473:pathology*; D051379:Mice; D009186:Myelin Sheath / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D012583:Schwann Cells / Q000737:chemistry / Q000166:cytology
chemical_list: D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse