Neurotrophins are key mediators of the myelination program in the peripheral nervous system

Abstract

Although knowledge of the functions of neurotrophins has advanced rapidly in recent years, studies concerning the involvement of neurotrophins in glial-neuronal interactions rarely extend further than their roles in supporting the survival and differentiation of neuronal cells. In this study endogenous brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) were identified in Schwann cell͞dorsal root ganglia neuronal cocultures and shown to modulate the myelination program of the peripheral nervous system. The differential expression of BDNF and NT3 were examined and compared with the expression profiles of myelin proteins in the cocultures throughout the myelination process. BDNF levels correlated with active myelin formation, whereas NT3 expression was initially high and then down regulated throughout the proliferation and premyelination periods. Addition of exogenous BDNF enhanced myelination, whereas the removal of the endogenous BDNF by using the BDNF receptor TrkB-Fc fusion protein inhibited the formation of mature myelin internodes. Interestingly, exogenous NT3 significantly inhibited myelination, whereas the removal of the endogenous NT3 by using the NT3 receptor TrkC-Fc fusion protein resulted in an enhancement similar to that obtained with the addition of BDNF. In addition, in vivo studies were performed during the development of the mouse sciatic nerve. Subcutaneous injections of BDNF resulted in an enhancement of myelin formation in the sciatic nerve, whereas the removal of the endogenous BDNF dramatically inhibited myelination. Injections of NT3 inhibited myelin formation, and the removal of the endogenous NT3 enhanced myelination. These results demonstrate that BDNF and NT3 possess different modulatory roles in the myelination program of the peripheral nervous system and that their mechanisms of action are specific and highly regulated. T he myelin sheath is a unique component of the nervous system that functions to maximize the efficiency and velocity of action potentials transmitted through nerve cell axons. The composition of myelin differs in the peripheral and central nervous systems principally in the nature of the proteins that are embedded in the lipid bilayers of the multiple myelin wraps. The proteins in peripheral myelin have received considerable attention because alterations in genes encoding these proteins are responsible for the demyelinating peripheral neuropathies, especially the Charcot-Marie-Tooth diseases (1). The formation of peripheral myelin is a complex, dynamic process involving two different cell types, the myelin forming glia (Schwann cells) and the neurons, that involve a series of neuronal-glial interactions controlling the various stages of myelination (2-4). Much has been learned about the interactions that define the three major phases of Schwann cell growth and differentiation in myelination. These include the proliferation and migration of Schwann cells on axons in the proliferative stage, the elongation and ensheathment of the axon by the Schwann cell in...

Glial Cell Line-Derived Neurotrophic Factor Alters Axon Schwann Cell Units and Promotes Myelination in Unmyelinated Nerve Fibers

“…Tissue-culture studies have shown that four agents, NGF (Wood et al, 1990;Bahr et al, 1991), progesterone (Koenig et al, 1995), insulin-like growth factor-1 (Russell et al, 1998), and brainderived nerve growth factor (Chan et al, 2001) can sustain or increase the myelination of small axons in vitro. Our in vitro data have shown that GDNF is another agent capable of sustaining the myelination of nerve fibers.…”

Internodes can nearly double in length with gradual elongation of the adult rat sciatic nerve

“…In culture, Schwann cells show three phases: proliferation, elongation & ensheathment, and myelination [4]. In vivo, after these phases, Schwann cells continue to elongate according to degree of bone growth [3].…”

“…In vivo, after these phases, Schwann cells continue to elongate according to degree of bone growth [3]. In a recent study, initiation of myelination was influenced by trophic factors such as neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta (TGF-P), or insulin-like growth factor-1 (IGF-I) [4,19], genes such as Krox-20 or Pax3 [19], or axon caliber [34]. Regulation of bone growth, which ceases with growth plate closure, is influenced by growth hormone or IGF-I [11, 14,18,21].…”

Rapid Effects of Retinoic Acid on CREB and ERK Phosphorylation in Neuronal Cells

“…Neuronal cultures were established from dorsal root ganglia (DRG) neurons obtained from Sprague Dawley rat embryos at 12 d gestation as described (Chan et al, 2001). DRG neurons were dissociated and plated onto collagencoated coverslips and were kept at 37°C in a medium consisting of 10% heat-inactivated FBS in MEM and 100 ng/ml NGF for one night.…”