Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome
Rett syndrome (RTT) is a neurodevelopmental disease in children that is mainly caused by mutations in the MeCP2 gene, which codes for a transcriptional regulator. The expression of insulin-like growth factor-1 (IGF-1) is reduced in RTT patients and animal models, and IGF-1 treatment is a promising t...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-01-01
|
Series: | Frontiers in Neuroscience |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00020/full |
id |
doaj-21cf668e75444d33a4fafbf106340f9e |
---|---|
record_format |
Article |
spelling |
doaj-21cf668e75444d33a4fafbf106340f9e2020-11-25T01:32:06ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-01-011410.3389/fnins.2020.00020494780Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett SyndromeZhe-Feng YuanShan-Shan MaoJue ShenLi-Hua JiangLu XuJia-Lu XuFeng GaoRett syndrome (RTT) is a neurodevelopmental disease in children that is mainly caused by mutations in the MeCP2 gene, which codes for a transcriptional regulator. The expression of insulin-like growth factor-1 (IGF-1) is reduced in RTT patients and animal models, and IGF-1 treatment is a promising therapeutic strategy for RTT. However, the mechanism underlying the effects of IGF-1 remains to be further explored. FXYD1 is an auxiliary subunit of Na, K-ATPase. Overexpression of FXYD1 is involved in the pathogenesis of RTT. However, whether IGF-1 exerts its effect through normalizing FXYD1 is completely unknown. To this end, we evaluated the effect of IGF-1 on FXYD1 expression and posttranslational modification in a mouse model of RTT (MeCP2308) using both in vitro and in vivo experiments. The results show that FXYD1 mRNA and phosphorylated protein (p-FXYD1) were significantly elevated in the frontal cortex in RTT mice, compared to wild type. In RTT mice, IGF-1 treatment significantly reduced levels of FXYD1 mRNA and p-FXYD1, in parallel with improvements in behavior, motor coordination, and cognitive function. For mechanistic insight into the effect of IGF-1 on p-FXYD1, we found the decreased phosphorylated forms of PI3K-AKT-mTOR signaling pathway components in the frontal cortex of RTT mice and the normalizing effect of IGF-1 on the phosphorylated forms of these components. Interestingly, blocking the PI3K/AKT pathway by PI3K inhibitor could abolish the effect of IGF-1 on p-FXYD1 level, in addition to the effect of IGF-1 on the phosphorylation of other components in the PI3K/AKT pathway. Thus, our study has provided new insights into the mechanism of IGF-1 treatment for RTT, which appears to involve FXYD1.https://www.frontiersin.org/article/10.3389/fnins.2020.00020/fullRett syndromeIGF-1MeCP2 mutant miceFXYD1neurodevelopmental disorders |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhe-Feng Yuan Shan-Shan Mao Jue Shen Li-Hua Jiang Lu Xu Jia-Lu Xu Feng Gao |
spellingShingle |
Zhe-Feng Yuan Shan-Shan Mao Jue Shen Li-Hua Jiang Lu Xu Jia-Lu Xu Feng Gao Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome Frontiers in Neuroscience Rett syndrome IGF-1 MeCP2 mutant mice FXYD1 neurodevelopmental disorders |
author_facet |
Zhe-Feng Yuan Shan-Shan Mao Jue Shen Li-Hua Jiang Lu Xu Jia-Lu Xu Feng Gao |
author_sort |
Zhe-Feng Yuan |
title |
Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome |
title_short |
Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome |
title_full |
Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome |
title_fullStr |
Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome |
title_full_unstemmed |
Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome |
title_sort |
insulin-like growth factor-1 down-regulates the phosphorylation of fxyd1 and rescues behavioral deficits in a mouse model of rett syndrome |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2020-01-01 |
description |
Rett syndrome (RTT) is a neurodevelopmental disease in children that is mainly caused by mutations in the MeCP2 gene, which codes for a transcriptional regulator. The expression of insulin-like growth factor-1 (IGF-1) is reduced in RTT patients and animal models, and IGF-1 treatment is a promising therapeutic strategy for RTT. However, the mechanism underlying the effects of IGF-1 remains to be further explored. FXYD1 is an auxiliary subunit of Na, K-ATPase. Overexpression of FXYD1 is involved in the pathogenesis of RTT. However, whether IGF-1 exerts its effect through normalizing FXYD1 is completely unknown. To this end, we evaluated the effect of IGF-1 on FXYD1 expression and posttranslational modification in a mouse model of RTT (MeCP2308) using both in vitro and in vivo experiments. The results show that FXYD1 mRNA and phosphorylated protein (p-FXYD1) were significantly elevated in the frontal cortex in RTT mice, compared to wild type. In RTT mice, IGF-1 treatment significantly reduced levels of FXYD1 mRNA and p-FXYD1, in parallel with improvements in behavior, motor coordination, and cognitive function. For mechanistic insight into the effect of IGF-1 on p-FXYD1, we found the decreased phosphorylated forms of PI3K-AKT-mTOR signaling pathway components in the frontal cortex of RTT mice and the normalizing effect of IGF-1 on the phosphorylated forms of these components. Interestingly, blocking the PI3K/AKT pathway by PI3K inhibitor could abolish the effect of IGF-1 on p-FXYD1 level, in addition to the effect of IGF-1 on the phosphorylation of other components in the PI3K/AKT pathway. Thus, our study has provided new insights into the mechanism of IGF-1 treatment for RTT, which appears to involve FXYD1. |
topic |
Rett syndrome IGF-1 MeCP2 mutant mice FXYD1 neurodevelopmental disorders |
url |
https://www.frontiersin.org/article/10.3389/fnins.2020.00020/full |
work_keys_str_mv |
AT zhefengyuan insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome AT shanshanmao insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome AT jueshen insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome AT lihuajiang insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome AT luxu insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome AT jialuxu insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome AT fenggao insulinlikegrowthfactor1downregulatesthephosphorylationoffxyd1andrescuesbehavioraldeficitsinamousemodelofrettsyndrome |
_version_ |
1725083208678113280 |