MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders
Abstract Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best‐defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscur...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-06-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201910270 |
| _version_ | 1797282513889001472 |
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| author | Angelisa Frasca Eleonora Spiombi Michela Palmieri Elena Albizzati Maria Maddalena Valente Anna Bergo Barbara Leva Charlotte Kilstrup‐Nielsen Federico Bianchi Valerio Di Carlo Ferdinando Di Cunto Nicoletta Landsberger |
| author_facet | Angelisa Frasca Eleonora Spiombi Michela Palmieri Elena Albizzati Maria Maddalena Valente Anna Bergo Barbara Leva Charlotte Kilstrup‐Nielsen Federico Bianchi Valerio Di Carlo Ferdinando Di Cunto Nicoletta Landsberger |
| author_sort | Angelisa Frasca |
| collection | DOAJ |
| description | Abstract Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best‐defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as “sensory antennae” protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium‐related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT‐related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target. |
| first_indexed | 2024-03-07T17:14:09Z |
| format | Article |
| id | doaj.art-b33103f72f62419ba99b856dddd50402 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:14:09Z |
| publishDate | 2020-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-b33103f72f62419ba99b856dddd504022024-03-02T23:49:31ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-06-01126n/an/a10.15252/emmm.201910270MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disordersAngelisa Frasca0Eleonora Spiombi1Michela Palmieri2Elena Albizzati3Maria Maddalena Valente4Anna Bergo5Barbara Leva6Charlotte Kilstrup‐Nielsen7Federico Bianchi8Valerio Di Carlo9Ferdinando Di Cunto10Nicoletta Landsberger11Department of Medical Biotechnology and Translational Medicine University of Milan Milan ItalyDepartment of Medical Biotechnology and Translational Medicine University of Milan Milan ItalyNeuroscience Division IRCCS San Raffaele Scientific Institute Milan ItalyDepartment of Medical Biotechnology and Translational Medicine University of Milan Milan ItalyDepartment of Biotechnology and Life Sciences Centre of Neuroscience University of Insubria Busto Arsizio ItalyDepartment of Biotechnology and Life Sciences Centre of Neuroscience University of Insubria Busto Arsizio ItalyDepartment of Biotechnology and Life Sciences Centre of Neuroscience University of Insubria Busto Arsizio ItalyDepartment of Biotechnology and Life Sciences Centre of Neuroscience University of Insubria Busto Arsizio ItalyNeuroscience Institute Cavalieri Ottolenghi Orbassano ItalyDepartment of Medical Biotechnology and Translational Medicine University of Milan Milan ItalyNeuroscience Institute Cavalieri Ottolenghi Orbassano ItalyDepartment of Medical Biotechnology and Translational Medicine University of Milan Milan ItalyAbstract Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best‐defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as “sensory antennae” protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium‐related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT‐related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target.https://doi.org/10.15252/emmm.201910270MeCP2primary ciliumRett syndromesonic hedgehogtubacin treatment |
| spellingShingle | Angelisa Frasca Eleonora Spiombi Michela Palmieri Elena Albizzati Maria Maddalena Valente Anna Bergo Barbara Leva Charlotte Kilstrup‐Nielsen Federico Bianchi Valerio Di Carlo Ferdinando Di Cunto Nicoletta Landsberger MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders EMBO Molecular Medicine MeCP2 primary cilium Rett syndrome sonic hedgehog tubacin treatment |
| title | MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders |
| title_full | MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders |
| title_fullStr | MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders |
| title_full_unstemmed | MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders |
| title_short | MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders |
| title_sort | mecp2 mutations affect ciliogenesis a novel perspective for rett syndrome and related disorders |
| topic | MeCP2 primary cilium Rett syndrome sonic hedgehog tubacin treatment |
| url | https://doi.org/10.15252/emmm.201910270 |
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