Abstract
Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K + channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 481-490 |
| Number of pages | 10 |
| Journal | Journal of Neuroscience Research |
| Volume | 80 |
| Issue number | 4 |
| DOIs | |
| State | Published - May 15 2005 |
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Keywords
- Granule neurons
- IGF-I
- Potassium channel
- Weaver mice
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice. / Zhong, Jin; Deng, Jixian; Phan, Jennifer; Dlouhy, Stephen; Wu, Huangbing; Yao, Weiguo; Ye, Ping; D'Ercole, A. Joseph; Lee, Wei Hua.
In: Journal of Neuroscience Research, Vol. 80, No. 4, 15.05.2005, p. 481-490.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice
AU - Zhong, Jin
AU - Deng, Jixian
AU - Phan, Jennifer
AU - Dlouhy, Stephen
AU - Wu, Huangbing
AU - Yao, Weiguo
AU - Ye, Ping
AU - D'Ercole, A. Joseph
AU - Lee, Wei Hua
PY - 2005/5/15
Y1 - 2005/5/15
N2 - Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K + channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.
AB - Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K + channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.
KW - Granule neurons
KW - IGF-I
KW - Potassium channel
KW - Weaver mice
UR - http://www.scopus.com/inward/record.url?scp=20344375969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20344375969&partnerID=8YFLogxK
U2 - 10.1002/jnr.20490
DO - 10.1002/jnr.20490
M3 - Article
C2 - 15846777
AN - SCOPUS:20344375969
VL - 80
SP - 481
EP - 490
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 4
ER -