Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF

Sendtner, Michael; Rudolf, G.; Holtmann, Bettina; Escary, Jean-Louis; Masu, Yasuo; Carroll, Patrick; Wolf, Eckhard; Brem, Gottfried; Brûlet, Philippe; Thoenen, H.

doi:10.1016/s0960-9822(09)00450-3

Cited by 158 publications

(124 citation statements)

References 46 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…Morphological changes associated with functional loss of CNTF, LIF, CT-1, or CNTF/LIF have been described previously (Masu et al, 1993;Banner and Patterson, 1994;Sendtner et al, 1996;Oppenheim et al, 2001). To elucidate how these neurotrophic cytokines act similarly or distinctly on postnatal maintenance of motoneurons, we analyzed cntf/lif/ct-1 tripleknock-out mice compared with cntf/lif double-knock-out, cntf/ct-1 doubleknock-out, and wild-type control mice.…”

Section: Motoneuron Loss In the Lumbar Spinal Cordmentioning

confidence: 98%

“…Gene-targeting experiments show that CNTF and LIF cooperate in maintaining postnatal survival and functional integrity of motoneurons and that LIF, although expressed only at low levels in peripheral nerves, contributes to compensatory mechanisms that prevent functional deficits in CNTF-deficient mice (Sendtner et al, 1996). This at least partial functional overlap is reflected by the fact that they share gp130 and LIF receptor ␤ (LIFR␤) as signal-transducing receptor components in responsible cells (Davis et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Holtmann¹,

Wiese²,

Samsam³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

Members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) gene family play an essential role for survival of developing and postnatal motoneurons. When subunits of the shared receptor complex are inactivated by homologous recombination, the mice die at approximately birth and exhibit reduced numbers of motoneurons in the spinal cord and brainstem nuclei. However, mice in which cntf, lif, or cardiotrophin-1 (ct-1) are inactivated can survive and show less motoneuron cell loss. This suggests cooperative and redundant roles of these ligands. However, their cooperative functions are not well understood. We generated cntf/lif/ct-1 triple-knockout and combinations of double-knock-out mice to study the individual and combined roles of CNTF, LIF and CT-1 on postnatal motoneuron survival and function. Triple-knock-out mice exhibit increased motoneuron cell loss in the lumbar spinal cord that correlates with muscle weakness during early postnatal development. LIF deficiency leads to pronounced loss of distal axons and motor endplate alterations, whereas CNTF-and/or CT-1-deficient mice do not show significant changes in morphology of these structures. In cntf/lif/ct-1 triple-knock-out mice, various degrees of muscle fiber type grouping are found, indicating that denervation and reinnervation had occurred. We conclude from these findings that CNTF, LIF, and CT-1 have distinct functions for motoneuron survival and function and that LIF plays a more important role for postnatal maintenance of distal axons and motor endplates than CNTF or CT-1.

show abstract

Section: Motoneuron Loss In the Lumbar Spinal Cordmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Holtmann¹,

Wiese²,

Samsam³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Transection of the facial nerve in the adult mouse is known to cause an easily visible late degeneration of 20-35% of the axotomized motor neurons (25). Mice were immunized with Cop-1 (n ϭ 10) or injected with PBS (n ϭ 9), both emulsified in CFA, and 7 days later were subjected to facial nerve axotomy.…”

Section: Cop-1 Vaccination Protects Against Motor Neuron Death Inducementioning

confidence: 99%

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Angelov

Waibel

Guntinas‐Lichius

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

179

104

View full text Add to dashboard Cite

Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu͞Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ؎ 7 days (n ‫؍‬ 15) to 263 ؎ 8 days (n ‫؍‬ 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

show abstract

“…The LIF receptor is also required for motor neuron development, but it is not yet clear if this corresponds to a dependence on LIF itself or another neuropoietic cytokine that utilizes the LIF receptor in its receptor complex [125]. Studies of double KO mice have shown that LIF and CNTF cooperate in the support of motor neurons in the normal adult mouse [127].…”

Section: Lif In Neural Inflammationmentioning

confidence: 99%

Leukemia Inhibitory Factor, Interleukin 6, and Other Cytokines Using the GP130 Transducing Receptor: Roles in Inflammation and Injury

1999

View full text Add to dashboard Cite

Inflammation refers to a complex set of mechanisms by which tissues respond to injury and infection. Among the many soluble mediators associated with this process, cytokines are known to be crucial in regulating a variety of cellular and molecular events. Leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL-11, and possibly other members of this cytokine family are key mediators in various inflammatory processes such as the acute-phase reaction, tissue damage, and infection. These cytokines can act in both pro-inflammatory and anti-inflammatory ways, depending on a number of variables. We emphasize here recent work utilizing knockout mice, which has highlighted the roles of LIF and IL-6, particularly in interactions between the immune and nervous systems.

show abstract

Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF

Cited by 158 publications

References 46 publications

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

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

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Leukemia Inhibitory Factor, Interleukin 6, and Other Cytokines Using the GP130 Transducing Receptor: Roles in Inflammation and Injury

Contact Info

Product

Resources

About