Konditionale Inaktivierung von Pten in einem neuen Mausmodell für tomaculöse Neuropathien

Abstract

Schwann cells in the peripheral nervous system form the myelin sheath by wrapping multiple membrane layers around axons with a diameter greater than 1 μm. Such ensheathment of the axon is considered an important prerequisite for an optimal nerve conduction velocity. A factor considered crucial for Schwann cell development and the initiation of myelination is the axonal EGF-like growth factor NRG1 type III, which binds the ERB2/3 receptor on Schwann cells. The PI3K-AKT pathway is a known downstream effector of ERB2/3-activation and has already been associated with myelination. To examine the role of PI3K-AKT signaling in Schwann cells, we generated mouse mutants by inactivating the gene Phosphatase and Tensin Homolog (Pten) in Schwann cells and oligodendrocytes using of the Cre/loxP-system (Pten-Mutants). The loss of the lipid- phosphatase PTEN resulted in an accumulation of its substrate, the second messenger Phosphatidyl-(3,4,5)-trisphosphate (PIP3), and consequently in an overactivation of the PI3K- AKT-pathway. We observed an ectopic myelination of normally unmyelinated C-fiber axons as well as a hypermyelination of axons up to a diameter of 2 μm in the Pten-Mutants. Axons greater than 2 μm in diameter showed myelin outfoldings and focal hypermyelinations (Tomacula) adjacent to regions of uncompact myelin (paranodal loops and Schmidt-Lantermann incisures). Additionally, mutant Remak Schwann cells formed uncompact membrane wrappings around normally unmyelinated C-fiber axons (‘Remak-myelin’) and even around collagen fibrils. An increased activity of the PI3K-AKT pathway could be detected in regions of uncompact myelin as well as in the Remak bundles of the Pten-Mutants. We presume that the accumulation of PIP3 with the increased PI3K-AKT-signaling triggers a cell-autonomous membrane wrapping of axons by mutant glial cells. The observation of ‘Remak- Myelin’ around collagen fibrils, which lack any membrane surface, indicates that this wrapping seems not to be dependent on bidirectional axo-glial signaling. The observed myelin outfoldings and Tomacula resembled hallmarks of mouse mutants for human hereditary neuropathies, like HNPP and CMT4B. We suggest that PTEN preserves regions of uncompact myelin against uncontrolled membrane growth and that a disturbed balance of PIP3 and other phosphoinositides might play a critical role in the pathology of different neuropathies. We therefore propose the PI3K-AKT-pathway as a possible target for future therapies against human hereditary neuropathies.