Peripheral myelination and the claw paw mice
1
NEWS AND VIEWS 14 VOLUME 9 | NUMBER 1 | JANUARY 2006 NATURE NEUROSCIENCE duce proapoptotic stimuli, including the Fas ligand (FasL) and TNF-α, and produce pro- inflammatory stimuli via cyclooxygenase-2 (COX-2) and iNOS upregulation 7 . Some of these microglial responses, like increased TNF-α production, are observed long before disease symptoms become apparent 8 , and isolated motor neurons from mutant Sod1 transgenic mouse models seem more sensi- tive to TNF-α and FasL 9 . Moreover, treat- ment of G93A Sod1 mice with minocycline, an agent that can inhibit microglial activa- tion 10 , is beneficial. Other groups have shown that the mutant SOD protein is present in the cerebrospinal fluid (CSF) of ALS patients, and that the CSF from ALS patients is toxic in mixed spinal cultures from embryonic rodents. Notably, minocycline inhibits the toxicity of CSF from ALS patients in such cultures 11 , indicating that microglial activa- tion is essential in this context. There is another potential implication of the finding that CgA and mutant SOD are released from motor neurons and possibly also from astrocytes. N-terminal peptides of CgA also act on blood vessels as antiangiogenic agents 12 . If the release of CgA and this peptide is enhanced in ALS1, then this could have harmful conse- quences on blood vessels and circulation in the spinal cord. This could then also explain the positive effect of vascular endothelial growth factor (VEGF) 13 , a protein that enhances the proliferation, migration and survival of vascu- lar endothelial cells, in rat and mouse models with mutant SOD1. In cell cultures of isolated and enriched motor neurons from embryonic rats or mice, VEGF has a small neuroprotec- tive effect 14 , but these effects are much more robust in vivo 13 , suggesting that additional effects on glial cells and the vasculature in the brain and spinal cord contribute to its thera- peutic effects. In this scheme, VEGF could counteract the harmful actions of CgA or its N-terminal peptide on blood vessels. However, it remains an open question whether alteration in the vasculature in the brain and spinal cord contributes to motor neuron disease in mouse models or patients with mutant SOD1. There are also other unanswered ques- tions. The receptors on microglia and motor neurons that mediate the toxic effect of CgA and mutant SOD1 are unknown. Moreover, genetic evidence for the proposed model of CgA involvement in the disease process is still missing. CgA knockout mice are available and show enhanced blood pressure caused by the unregulated release of catecholamines from chromaffin cells and noradrenaline- producing sympathetic neurons 15 . Crossing these mice with mutant Sod1 transgenic mice would be a worthwhile endeavor. Although microglial activation is a common feature of many (if not all) forms of ALS, it is also not known whether CgA is involved in other forms of motor neuron disease that are not caused by mutations in SOD1. The findings by Urushitani et al. that extra- cellular mutant SOD1 protein is involved in the activation of microglia and is directly toxic for motor neurons may also have broader clinical implications, at least for the subgroup of patients with ALS1. If extracellular mutant SOD1 contributes to the disease mechanism, then there is a strong rationale to develop therapeutic approaches on the basis of the clearance of extracellular mutant SOD1. By identifying a new pathogenic mechanism, Urushitani et al. have, at the very least, broad- ened our horizons for devising potential thera- peutic targets for this devastating disease. 1. Bruijn, L.I., Miller, T.M. & Cleveland, D.W. Annu. Rev. Neurosci. 27, 723–749 (2004). 2. Clement, A.M. et al. Science 302, 113–117 (2003). 3. Urushitani, M. et al. Nat. Neurosci. 9, 108–118 (2006). 4. Pasinelli, P. et al. Neuron 43, 19–30 (2004). 5. Taupenot, L., Harper, K.L. & O’Connor, D.T. N. Engl. J. Med. 348, 1134–1149 (2003). 6. Ciesielski-Treska, J. et al. J. Biol. Chem. 273, 14339– 14346 (1998). 7. Sargsyan, S.A., Monk, P.N. & Shaw, P.J. Glia 51, 241–253 (2005). 8. Yoshihara, T. et al. J. Neurochem. 80, 158–167 (2002). 9. Raoul, C. et al. Neuron 35, 1067–1083 (2002). 10. Van Den Bosch, L., Tilkin, P., Lemmens, G. & Robberecht, W. Neuroreport 13, 1067–1070 (2002). 11. Tikka, T.M. et al. Brain 125, 722–731 (2002). 12. Mandala, M., Brekke, J.F., Serck-Hanssen, G., Metz- Boutigue, M.H. & Helle, K.B. Regul. Pept. 124, 73–80 (2005). 13. Storkebaum, E. et al. Nat. Neurosci. 8, 85–92 (2005). 14. Van Den Bosch, L. et al. Neurobiol. Dis. 17, 21–28 (2004). 15. Mahapatra, N.R. et al. J. Clin. Invest. 115, 1942– 1952 (2005). Peripheral myelination and the claw paw mice Due to a spontaneously occurring recessive mutation, claw paw (clp) mice have peripheral hypomyelination, axon sorting deficits and abnormal limb posture. Because their phenotype is specific to the peripheral nervous system, these mice provide an attractive model for studying Schwann cell development and Schwann cell-axon interactions. On page 76 of this issue, Bermingham and colleagues have identified the molecular basis of this mutation as well as a new signaling molecule in peripheral nerve development. The authors used positional cloning to localize the mutation to Lgi4, a member of the leucine-rich, glioma inactivated (Lgi) family of genes encoding putative secreted proteins of unknown function. They find that claw paw mice have a 225 base pair insertion in Lgi4, leading to a protein that lacks exon 4. Lgi4 is expressed primarily in Schwann cells in the peripheral nervous system. As suggested by its structure, the authors show that it is a secreted protein, but that the claw paw mutation causes it to be retained in the endoplasmic reticulum.Cultures containing neurons and Schwann cells from claw paw mice had reduced myelination and Schwann cell maturation, and conditioned media from cells expressing wild-type Lgi4 rescued these deficits, suggesting the claw paw phenotype results from reduced Lgi4 secretion. These results provide new insights into the signaling mechanisms involved in peripheral nerve development and may point to Lgi4 as a potential therapeutic target for stimulating myelina- tion in injury or disease. Cara Allen © 2006 Nature Publishing Group http://www.nature.com/natureneuroscience
Transcript of Peripheral myelination and the claw paw mice
N E W S A N D V I E W S
14 VOLUME 9 | NUMBER 1 | JANUARY 2006 NATURE NEUROSCIENCE
duce proapoptotic stimuli, including the Fas ligand (FasL) and TNF-α, and produce pro-inflammatory stimuli via cyclooxygenase-2 (COX-2) and iNOS upregulation7. Some of these microglial responses, like increased TNF-α production, are observed long before disease symptoms become apparent8, and isolated motor neurons from mutant Sod1 transgenic mouse models seem more sensi-tive to TNF-α and FasL9. Moreover, treat-ment of G93A Sod1 mice with minocycline, an agent that can inhibit microglial activa-tion10, is beneficial. Other groups have shown that the mutant SOD protein is present in the cerebrospinal fluid (CSF) of ALS patients, and that the CSF from ALS patients is toxic in mixed spinal cultures from embryonic rodents. Notably, minocycline inhibits the toxicity of CSF from ALS patients in such cultures11, indicating that microglial activa-tion is essential in this context.
There is another potential implication of the finding that CgA and mutant SOD are released from motor neurons and possibly also from astrocytes. N-terminal peptides of CgA also act on blood vessels as antiangiogenic agents12. If the release of CgA and this peptide is enhanced in ALS1, then this could have harmful conse-quences on blood vessels and circulation in the spinal cord. This could then also explain the positive effect of vascular endothelial growth factor (VEGF)13, a protein that enhances the proliferation, migration and survival of vascu-lar endothelial cells, in rat and mouse models
with mutant SOD1. In cell cultures of isolated and enriched motor neurons from embryonic rats or mice, VEGF has a small neuroprotec-tive effect14, but these effects are much more robust in vivo13, suggesting that additional effects on glial cells and the vasculature in the brain and spinal cord contribute to its thera-peutic effects. In this scheme, VEGF could counteract the harmful actions of CgA or its N-terminal peptide on blood vessels. However, it remains an open question whether alteration in the vasculature in the brain and spinal cord contributes to motor neuron disease in mouse models or patients with mutant SOD1.
There are also other unanswered ques-tions. The receptors on microglia and motor neurons that mediate the toxic effect of CgA and mutant SOD1 are unknown. Moreover, genetic evidence for the proposed model of CgA involvement in the disease process is still missing. CgA knockout mice are available and show enhanced blood pressure caused by the unregulated release of catecholamines from chromaffin cells and noradrenaline-producing sympathetic neurons15. Crossing these mice with mutant Sod1 transgenic mice would be a worthwhile endeavor. Although microglial activation is a common feature of many (if not all) forms of ALS, it is also not known whether CgA is involved in other forms of motor neuron disease that are not caused by mutations in SOD1.
The findings by Urushitani et al. that extra-cellular mutant SOD1 protein is involved in
the activation of microglia and is directly toxic for motor neurons may also have broader clinical implications, at least for the subgroup of patients with ALS1. If extracellular mutant SOD1 contributes to the disease mechanism, then there is a strong rationale to develop therapeutic approaches on the basis of the clearance of extracellular mutant SOD1. By identifying a new pathogenic mechanism, Urushitani et al. have, at the very least, broad-ened our horizons for devising potential thera-peutic targets for this devastating disease.
1. Bruijn, L.I., Miller, T.M. & Cleveland, D.W. Annu. Rev. Neurosci. 27, 723–749 (2004).
2. Clement, A.M. et al. Science 302, 113–117 (2003). 3. Urushitani, M. et al. Nat. Neurosci. 9, 108–118
(2006).4. Pasinelli, P. et al. Neuron 43, 19–30 (2004).5. Taupenot, L., Harper, K.L. & O’Connor, D.T. N. Engl.
J. Med. 348, 1134–1149 (2003).6. Ciesielski-Treska, J. et al. J. Biol. Chem. 273, 14339–
14346 (1998).7. Sargsyan, S.A., Monk, P.N. & Shaw, P.J. Glia 51,
241–253 (2005).8. Yoshihara, T. et al. J. Neurochem. 80, 158–167
(2002).9. Raoul, C. et al. Neuron 35, 1067–1083 (2002).10. Van Den Bosch, L., Tilkin, P., Lemmens, G. &
Robberecht, W. Neuroreport 13, 1067–1070 (2002).
11. Tikka, T.M. et al. Brain 125, 722–731 (2002).12. Mandala, M., Brekke, J.F., Serck-Hanssen, G., Metz-
Boutigue, M.H. & Helle, K.B. Regul. Pept. 124, 73–80 (2005).
13. Storkebaum, E. et al. Nat. Neurosci. 8, 85–92 (2005).
14. Van Den Bosch, L. et al. Neurobiol. Dis. 17, 21–28 (2004).
15. Mahapatra, N.R. et al. J. Clin. Invest. 115, 1942–1952 (2005).
Peripheral myelination and the claw paw mice
Due to a spontaneously occurring recessive mutation, claw paw (clp) mice have peripheral hypomyelination, axon sorting deficits and abnormal limb posture. Because their phenotype is specific to the peripheral nervous system, these mice provide an attractive model for studying Schwann cell development and Schwann cell-axon interactions. On page 76 of this issue, Bermingham and colleagues have identified the molecular basis of this mutation as well as a new signaling molecule in peripheral nerve development.
The authors used positional cloning to localize the mutation to Lgi4, a member of the leucine-rich, glioma inactivated (Lgi) family of genes encoding putative secreted proteins of unknown function. They find that claw paw mice have a 225 base pair insertion in Lgi4, leading to a protein that lacks exon 4. Lgi4 is expressed primarily in Schwann cells in the peripheral nervous system. As suggested by its structure, the authors show that it is a secreted protein, but that the claw paw mutation causes it to be retained in the endoplasmic reticulum.Cultures containing neurons and Schwann cells from claw paw mice had reduced myelination and Schwann cell maturation, and conditioned media from cells expressing wild-type Lgi4 rescued these deficits, suggesting the claw paw phenotype results from reduced Lgi4 secretion. These results provide new insights into the signaling mechanisms involved in peripheral nerve development and may point to Lgi4 as a potential therapeutic target for stimulating myelina-tion in injury or disease.
Cara Allen
©20
06 N
atur
e P
ublis
hing
Gro
up
http
://w
ww
.nat
ure.
com
/nat
uren
euro
scie
nce
![Peripheral modifications of [Ψ[CH NH]Tpg4]vancomycin ...](https://static.fdocument.org/doc/165x107/6211b4c5b9a3d33a3c037f89/peripheral-modifications-of-ch-nhtpg4vancomycin-.jpg)
