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Motoneurons played an essential role in establishing the concept of target-mediated support of innervating neurons. However, it took several decades until molecules were identined which trophically support motoneurons in vitro and in vivo. The most potent molecule identined so far is ciliary neurotrophic factor (CNTF). It is expressed as a cytosolic molecule in myelinating Schwann cells rather than in skeletal muscle in the postnatal period and therefore does not qualify as a target-derived neurotrophic factor regulating motoneuron survival during embryonic development. However, the inactivation of CNTF by gene targeting experiments results in progressive atrophy and degeneration of motoneurons, demonstrating that CNTF plays an essential role as a maintenance factor for motoneurons postnatally. Secretory molecules which are expressed in skeletal muscle during embryonic development and which support motoneurons in culture and partially also in vivo include members of the NGF gene family (BDNF, NT-3, NT-4/S) , FGF-S, IGF-I, and UF. The evaluation of the physiological importance of these molecules is under investigation.
The survival and functional maintenance of spinal motoneurons, both during the period of developmental cell death and in adulthood, have been shown to be dependent on trophic factors. In vitro experiments have previously been used to identify several survival factors for motoneurons, including CNTF, UF, and members of the neurotrophin, FGF, and IGF gene families. Some of these factors have also been shown to be active in vivo, either on chick motoneurons during embryonic development or on lesioned facial and spinal motoneurons of the newborn rat. Here we demonstrate that lesioned newborn rat facial motoneurons can be rescued by NT-4/5, IGF-I, and UF. Furthermore, in contrast to chick motoneurons, the survival of isolated embryonic rat motoneurons can be maintained by the neurotrophins BDNF, NT-3, and NT-4/5. IGF-I and FGF-5 were also active in this system, each supporting more than 50% of the originally plated neurons. The responsiveness of motoneurons to multiple factors in vitro and in vivo suggests that motoneuron survival and function are regulated by the coordinated actions of members of different gene families.
We showed previously that oligodendrocytes and their precursors require continuous signalling by protein trophic factors to avoid programmed cell death in culture. Here we show that three classes of such trophic factors promote oligodendrocyte survival in vitro: (1) insulin and insulin-like growth factors (IGFs), (2) neurotrophins, particularly neurotrophin-3 (NT -3), and (3) ciliary-neurotrophic factor (CNTF), leukemia inhibitory factor (LIF) and interleukin 6 (IL-6). A single factor, or combinations of factors within the same class, promote only short-term survival of oligodendrocytes and their precursors, while combinations of factors from different classes promote survival additively. Long-term survival of oligodendrocytes in vitro requires at least one factor from each class, suggesting that multiple signals may be required for long-term oligodendrocyte survival in vivo. We also show that CNTF promotes oligodendrocyte survival in vivo, that platelet-derived growth factor (PDGF) can promote the survival of oligodendrocyte precursors in vitro by acting on a novel, very high affinity PDGF receptor, and that, in addition to its effect on survival, NT-3 is a potent mitogen for oligodendrocyte precursor cells.
Ciliary neurotrophic factor (CNTF) is expressed in high quantities in Schwann cells of peripheral nerves during postnatal development of the rat. The absence of a hydrophobic leader sequence and the immunohistochemical localization of CNTF within the cytoplasm of these cells indicate that the factor might not be available to responsive neurons under physiological conditions. However, CNTF supports the survival of a variety of embryonic neurons, including spinal motoneurons in culture. Moreover we have recently demonstrated that the exogenous application of CNTF protein to the lesioned facial nerve of the newborn rat rescued these motoneurons from cell death. These results indicate that CNTF might indeed play a major role in assisting the survival of lesioned neurons in the adult peripheral nervous system. Here we demonstrate that the CNTF mRNA and protein levels and the manner in which they are regulated are compatible with such a function in lesioned peripheral neurons. In particular, immunohistochemical analysis showed significant quantities of CNTF at extracellular sites after sciatic nerve lesion. Western blots and determination of CNTF biological activity of the same nerve segments indicate that extracellular CNTF seems to be biologically active. After nerve lesion CNTF mRNA levels were reduced to <5 % in distal regions of the sciatic nerve whereas CNTF bioactivity decreased to only one third of the original before-lesion levels. A gradual reincrease in Schwann cells occurred concomitant with regeneration.
CILIARY neurotrophic factor (CNTF) supports the survival of embryonic motor neurons in vitro and in vivo and prevents lesion-mediated degeneration of rat motor neuron~ during early post-natal stages. Here we report that CNTF greatly reduces all the functional and morphological changes in pmnlpmn mice5, an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration. The first manifestations of progressive motor neuronopathy in homozygous pmnl pmn mice become apparent in the hind limbs at the end of the third post-natal week and all the mice die up to 6 or 7 weeks after birth from respiratory paralysis. Treatment with CNTF prolongs- survival- and greatly Impoves motor function of these mice. Moreover, morphological manifestations, such as loss of motor axons in the phrenic nerve and degeneration of facial motor neurons, were greatly reduced by CNTF, although the treatment did not start until the first symptoms of the disease had already become apparent and substantial degenerative changes were already present. The protective and restorative effects of CNTF in this mouse mutant give new perspectives for the treatment of human degenerative motor neuron diseases with CNTF.
Motoneurons innervating the skeletal musculature were among the first neurons shown to require the presence of their target cells to develop appropriatelyl,2. But the characterization of molecules allowing motoneuron survival has been difficult. Ciliary neurotrophic factor prevents the death of motoneurons3-6, but its gene is not expressed during development7. Although the presence of a neurotrophin receptor on developing motoneurons8-1O has suggested a role for neurotrophins, none could be shown to promote motoneuron survival in vitro3. We report here that brainderived neurotrophic factor can prevent the death of axotomized motoneurons in newborn rats, suggesting a role for this neurotrophin for motoneuron survival in vivo.
More on motor neurons
(1992)
Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a variety of embryonic neurons in culture. The developmental expression of CNTF occurs clearly after the time period of the physiological cell death of CNTF-responsive neurons. This, together with the sites of expression, excludes CNTF as a target-derived neuronal survival factor, at least in rodents. However, CNTF also participates in the induction of type 2 astrocyte differentiation in vitro. Here we demonstrate that the time course of the expression of CNTF-mRNA and protein in the rat optic nerve (as evaluated by quantitative Northern blot analysis and biological activity, respectively) is compatible with such a glial differentiation function of CNTF in vivo. We also show that the type 2 astrocyte-inducing- activity previously demonstrated in optic nerve extract can be precipitated by an antiserum against CNTF. Immunohistochemical analysis of astrocytes in vitro and in vivo demonstrates that the expression of CNTF is confined to a subpopulation of type 1 astrocytes. The olfactory bulb of adult rats has comparably high levels of CNTF to the optic nerve, and here again, CNTF-immunoreactivity is localized in a subpopulation of astrocytes. However, the postnatal expression of CNTF in the olfactory bulb occurs later than in the optic nerve. In other brain regions both CNTF-mRNA and protein levels are much lower.
We have demonstrated that the extensive degeneration of motoneurons in the rat facial nucleus after transection of the facial nerve in newborn rats can be prevented by local ciliary neurotrophic factor (CNTF) administration. CNTF differs distinctly from known neurotrophic molecules such as NGF, BDNF and NT-3 in both its molecular characteristics (CNTF is a cytosolic rather than a secretory molecule) and its broad spectrum of biological activities. CNTF is expressed selectively by Schwann cells and astrocytes of the peripheral and central nervous system, respectively, but not by target tissues of the great variety of CNTF -responsive neurons. CNTF mRNA is not detectable by Northern blot or PCR analysis during embryonic development and immediately after birth. However, during the second post-natal week, a more than 30-fold increase in CNTF mRNA and pro tein occurs in the sciatic nerve. Since the period of low CNTF levels in peripheral nerves coincides with that of high vulnerability of motoneurons (i.e. axonallesion results in degeneration of motoneuron cell bodies), insufficient availability of CNTF may be the reason for the rate of lesioninduced cell death of early post-natal motoneurons. Highly enriched embryonic chick motoneurons in culture are supported at survival rates higher than 60% by CNTF, even in single cell cultures, indicating that CNTF acts directly on motoneurons. In contrast to CNTF, the members of the neurotrophin gene family (NGF, BDNF and NT-3) do not support the survival of motoneurons in culture. However, aFGF and bFGF show distinct survival activities which are additive to those of CNTF, resulting in the survival of virtually all motoneurons cultured in the presence of CNTF and bFGF.