The adult mammalian peripheral nervous system (PNS) harbors an exceptional
plasticity, which allows the successful regeneration of axons and a subsequent functional recovery. Nerve repair is realized by a transdifferentiation of PNS glial cells, the Schwann cells, which
guide axonal regrowth and restore the electrically insulating myelin sheath necessary for rapid impulse propagation. Our research group focusses on the molecular mechanisms and cellular
interactions that orchestrate peripheral nerve regeneration. We envision that the response of Schwann cells and axons to acute nerve injury is likewise integral part of chronic peripheral nerve
diseases, such as hereditary or metabolic neuropathies. Translating the repair strategy of acutely damaged nerves to chronic PNS diseases helps us to gain new insight into the pathomechanisms of
peripheral neuropathies and to develop therapeutic strategies that promote nerve integrity and function.
Neuregulin-1 belongs to a family of transmembrane and secreted growth factors and is crucial for the development of different organs in mammals such as heart, lung and the nervous system. Neuregulin-1 expressed by neurons controls almost all steps of Schwann cell development in the peripheral nervous system. However, after acute nerve injury, Neuregulin-1 expression switches from neurons to glia, where it contributes to nerve repair and remyelination. In the central nervous system, the role of Neuregulin-1 in myelin formation and regeneration is even more complex. We aim at dissecting the function of Neuregulin-1 in different cell types, with a special focus on bidirectional axo-glia signaling and on downstream molecular mechanisms in both, the peripheral and central nervous system.
Stacked confocal images demonstrating remyelinating Schwann cells which induce the expression of the growth factor Neuregulin-1 after acute nerve injury. (MPZ = myelin protein zero, illustrating the myelin sheath, NRG1 C-term = antibody against the intracellular C-terminus of Neuregulin-1, DAPI = nuclear counterstaining, sclae = 20 µm and 3.5 µm in blow up)
Schwann cells demonstrate an enormous plasticity in the adult peripheral nervous system, which is characterized by a transdifferentiation from mature, adult glial cells into a precursor-like cell types after acute nerve injury. Although this process is well described for acute nerve injury, the role of these phenotypic changes of Schwann cells in chronic nerve diseases is much less well understood. We here aim at understanding the response of Schwann cells in different peripheral nerve diseases with a special emphasis on the functional contribution on nerve pathology and repair. What triggers Schwann cell transdifferentiation in demyelinating and axonal diseases of the PNS? Why does remyelination often fail in chronically injured peripheral nerve? How does Schwann cell plasticity contribute to axonal function and regeneration? In order to answer these questions, we take advantage of different animal models for peripheral nerve injuries combined with in-vitro systems of myelinating glia-neuron co-cultures. Finally, we envisage to identify new therapeutic targets for peripheral nerve diseases.
Myelinating co-culture system of DRG and Schwann cells. In green, myelinated internodes are visualized (antibody against myelin basic protein), together with axons in red (antibody against neurofilament) and Schwann cell nuclei (DAPI) in blue. Right: merge of all three channels.
Myelin loss in the central nervous system arises as a consequence of autoimmune, infectious, genetic and toxic diseases. However, the underlying mechanisms of demyelination and oligodendrocyte changes are still only poorly understood. We here aim at understanding the role of the myelin sheath and the myelinating, mature oligodendrocyte for the development of these diseases. Furthermore, we are interested in the axon-glia interaction during early disease stages and the implication of myelin for axonal function. For our research, we are taking advantage of mouse models for autoimmune encephalomyelitis, leukodystrophies and toxin-induced demyelination in the central nervous system.
Schematic representation of the lysolecithin model of toxin-induced demyelination, which allows to study a defined, focally demyelinated area in the ventrolateral spinal cord. Left: unaffected myelinated axons on the contralateral side. Right: light-microscopic overview of the demyelinated lesion and adjycent normal appearing white and grey matter.