Early onset of degenerative changes at nodes of Ranvier in alpha‐motor axons of Cntf null (^−/−) mutant mice

Abstract

The nodes of Ranvier are sites of specific interaction between Schwann cells and axons. Besides their crucial role in transmission of action potentials, the nodes of Ranvier and in particular the paranodal axon-Schwann cell networks (ASNs) are thought to function as local centers in large motor axons for removal, degradation, and disposal of organelles. In order to test whether ciliary neurotrophic factor (CNTF), which is present at high levels in the Schwann cell cytoplasm, is involved in the maintenance of these structures, we have examined lumbar ventral root nerve fibers of alpha-motor neurons by electron microscopy in 3- and 9-month-old Cntf null ((-/-)) mutant mice. Nerve fibers and nodes of Ranvier in 3-month-old Cntf(-/-) mutants appeared morphologically normal, except that ASNs were more voluminous in the mutants than in wild-type control animals at this age. In 9-month-old Cntf(-/-) animals, morphological changes, such as reduction in nerve fiber and axon diameter, myelin sheath disruption, and loss of ASNs at nodes of Ranvier, were observed. These findings suggest that endogenous CNTF, in addition to its role in promoting motor neuron survival and regeneration, is needed for long-term maintenance of alpha-motor nerve fibers. The premature loss of paranodal ASNs in animals lacking CNTF, which seems to be a defect related to a disturbed interaction in the nodal region between the axon and its myelinating Schwann cells, could impede the maintenance of a normal milieu in the motor axon, preceding more general neuronal damage.

Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells

“…Thus, reduced gene expression might be more critical in humans in comparison to mice. In postnatal CntfϪ͞Ϫ mice, loss of motoneurons occurs (17), and degenerative alterations in Schwann cell morphology such as disintegration of paranodal networks are detectable at nodes of Ranvier (42). Furthermore, reduced Cntf levels exaggerate the disease phenotype when combined with the superoxide dismutase 1 (SOD1) (19) gene mutation resulting in more severe motoneuron disease.…”

Ciliary Neurotrophic Factor Improves Nerve Conduction and Ameliorates Regeneration Deficits in Diabetic Rats

“…In vitro, CNTF supports survival of DRG neurons and maintains Na ϩ /K ϩ -ATPase activity (28). A role for CNTF in the development or maintenance of peripheral nerve is also suggested by decreased axonal caliber, myelin sheath disruption, and loss of axon-Schwann cell networks at the node of Ranvier observed in Cntf null ( Ϫ/Ϫ ) mice (12). In the present study, the amelioration of nerve conduction deficits in rats with established diabetes was associated with a partial restoration of mean axonal caliber but not a significant shift in axonal size-frequency distribution toward larger myelinated fibers.…”

Triple Knock-Out ofCNTF,LIF, andCT-1Defines Cooperative and Distinct Roles of these Neurotrophic Factors for Motoneuron Maintenance and Function

“…Members of the ciliary neurotrophic factor (CNTF )-leukemia inhibitory factor (LIF ) gene family are potent survival factors for motoneurons in vitro and in vivo (Arakawa et al, 1990;Sendtner et al, 1990;Hughes et al, 1993;Banner and Patterson, 1994;Pennica et al, 1996). At least CNTF plays an essential role for long-term maintenance of axons and paranodal networks, structures that are formed by the Schwann cells and axons near the nodes of Ranvier (Gatzinsky et al, 2003). This factor also protects axons under pathophysiological conditions, i.e., in progressive motoneuronopathy mutant mice (Sendtner et al, 1992a) and in experimental autoimmune encephalomyelitis (Linker et al, 2002).…”