The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons
Mutations in the human X-linked gene MECP2 are responsible for most Rett syndrome (RTT) cases, predominantly within its methyl-CpG-binding domain (MBD). To examine the role of MBD in the pathogenesis of RTT, we generated two MeCP2 mutant constructs, one with a deletion of MBD (MeCP2-ΔMBD), another...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-04-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2015.00158/full |
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| author | Na eZhao Na eZhao Dongliang eMa Wan Ying eLeong Ju eHan Antonius eVanDongen Antonius eVanDongen Teng eChen Eyleen L Goh Eyleen L Goh Eyleen L Goh |
| author_facet | Na eZhao Na eZhao Dongliang eMa Wan Ying eLeong Ju eHan Antonius eVanDongen Antonius eVanDongen Teng eChen Eyleen L Goh Eyleen L Goh Eyleen L Goh |
| author_sort | Na eZhao |
| collection | DOAJ |
| description | Mutations in the human X-linked gene MECP2 are responsible for most Rett syndrome (RTT) cases, predominantly within its methyl-CpG-binding domain (MBD). To examine the role of MBD in the pathogenesis of RTT, we generated two MeCP2 mutant constructs, one with a deletion of MBD (MeCP2-ΔMBD), another mimicking a mutation of threonine 158 within the MBD (MeCP2-T158M) found in RTT patients. MeCP2 knockdown resulted in a decrease in total dendrite length, branching, synapse number, as well as altered spontaneous Ca2+ oscillations in vitro, which could be reversed by expression of full length human MeCP2 (hMeCP2-FL). However, the expression of hMeCP2-ΔMBD in MeCP2-silenced neurons did not rescue the changes in neuronal morphology and spontaneous Ca2+ oscillations, while expression of hMeCP2-T158M in these neurons could only rescue the decrease in dendrite length and branch number. In vivo over expression of hMeCP2-FL but not hMeCP2-ΔMBD in adult newborn neurons of the dentate gyrus also rescued the cell autonomous effect caused by MeCP2 deficiency in dendrites length and branching. Our results demonstrate that an intact and functional MBD is crucial for MeCP2 functions in cultured hippocampal neurons and adult newborn neurons. |
| first_indexed | 2024-12-11T08:32:34Z |
| format | Article |
| id | doaj.art-648e0671faf64b01924ffb5ce0fb2de4 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T08:32:34Z |
| publishDate | 2015-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-648e0671faf64b01924ffb5ce0fb2de42022-12-22T01:14:26ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022015-04-01910.3389/fncel.2015.00158138429The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neuronsNa eZhao0Na eZhao1Dongliang eMa2Wan Ying eLeong3Ju eHan4Antonius eVanDongen5Antonius eVanDongen6Teng eChen7Eyleen L Goh8Eyleen L Goh9Eyleen L Goh10Duke-NUS Graduate Medical SchoolXi’an Jiaotong University School of MedicineDuke-NUS Graduate Medical SchoolDuke-NUS Graduate Medical SchoolDuke-NUS Graduate Medical SchoolDuke-NUS Graduate Medical SchoolNational University of SingaporeXi’an Jiaotong University School of MedicineDuke-NUS Graduate Medical SchoolNational University of SingaporeKK Women’s and Children’s HospitalMutations in the human X-linked gene MECP2 are responsible for most Rett syndrome (RTT) cases, predominantly within its methyl-CpG-binding domain (MBD). To examine the role of MBD in the pathogenesis of RTT, we generated two MeCP2 mutant constructs, one with a deletion of MBD (MeCP2-ΔMBD), another mimicking a mutation of threonine 158 within the MBD (MeCP2-T158M) found in RTT patients. MeCP2 knockdown resulted in a decrease in total dendrite length, branching, synapse number, as well as altered spontaneous Ca2+ oscillations in vitro, which could be reversed by expression of full length human MeCP2 (hMeCP2-FL). However, the expression of hMeCP2-ΔMBD in MeCP2-silenced neurons did not rescue the changes in neuronal morphology and spontaneous Ca2+ oscillations, while expression of hMeCP2-T158M in these neurons could only rescue the decrease in dendrite length and branch number. In vivo over expression of hMeCP2-FL but not hMeCP2-ΔMBD in adult newborn neurons of the dentate gyrus also rescued the cell autonomous effect caused by MeCP2 deficiency in dendrites length and branching. Our results demonstrate that an intact and functional MBD is crucial for MeCP2 functions in cultured hippocampal neurons and adult newborn neurons.http://journal.frontiersin.org/Journal/10.3389/fncel.2015.00158/fullDendritesnewborn neuronsRett Syndrome (RTT)spontaneuos Ca2+ oscillationmethyl-CpG binding protein 2 (MeCP2) |
| spellingShingle | Na eZhao Na eZhao Dongliang eMa Wan Ying eLeong Ju eHan Antonius eVanDongen Antonius eVanDongen Teng eChen Eyleen L Goh Eyleen L Goh Eyleen L Goh The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons Frontiers in Cellular Neuroscience Dendrites newborn neurons Rett Syndrome (RTT) spontaneuos Ca2+ oscillation methyl-CpG binding protein 2 (MeCP2) |
| title | The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons |
| title_full | The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons |
| title_fullStr | The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons |
| title_full_unstemmed | The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons |
| title_short | The Methyl-CpG-binding domain (MBD) is crucial for MeCP2’s dysfunction-induced defects in adult newborn neurons |
| title_sort | methyl cpg binding domain mbd is crucial for mecp2 s dysfunction induced defects in adult newborn neurons |
| topic | Dendrites newborn neurons Rett Syndrome (RTT) spontaneuos Ca2+ oscillation methyl-CpG binding protein 2 (MeCP2) |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2015.00158/full |
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