Onion bulb cells in mice deficient for myelin genes share molecular properties with immature, differentiated non-myelinating, and denervated Schwann cells

Onion bulb formation is a pathological feature observed in peripheral nerves of patients suffering from inherited peripheral neuropathies such as CharcotMarie-Tooth and Dejerine-Sottas diseases. An onion bulb consists of small circumferentially oriented (supernumerary) cells and their processes surrounding a large caliber axon. In the present study, we investigated the molecular phenotype of supernumerary cells at the light and electron microscopic levels. The major motor (quadriceps muscle) branch of the femoral nerve from 16- to 24-month-old mice with an inactivated allele of the myelin protein zero gene or deficient for myelin-associated glycoprotein (MAG; P0⁺ and MAG mice, respectively), which have numerous onion bulbs, was teased to obtain single nerve fibers, which were then processed for immunocytochemistry. Corresponding nerves from wild-type mice served as controls. In both P0⁺ and MAG^- mice, supernumerary cells expressed S-100, the low-affinity nerve growth factor receptor (p75, NGFr), the cell adhesion molecule L1, the neural cell adhesion molecule (N-CAM), and glial fibrillary acidic protein (GFAP). At the electron microscopic level, the cell surface of supernumerary cells was NGFr immunoreactive and L1 and N-CAM were expressed at points of contact between supernumerary cells. NGFr, L1, and N- CAM were also present in the basal lamina surrounding myelinated axons associated with onion bulbs. Both S-100 and GFAP immunoreactivities were seen in the cytoplasm of supernumerary cells. In contrast, in wild-type mice myelinating Schwann cells only expressed S-100 intracellularly and L1 and N- CAM in their basal lamina, whereas non-myelinating Schwann cells expressed all five molecules investigated. The present study indicates that supernumerary cells in onion bulbs have a molecular phenotype characteristic of immature, differentiated non-myelinating, and denervated Schwann cells, thus excluding the possibility that supernumerary cells are perineurial cells.