FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm.
Fragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of sp...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-12-01
|
| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002417&type=printable |
| _version_ | 1827400202746593280 |
|---|---|
| author | Suna Jung Sneha Shah Geongoo Han Joel D Richter |
| author_facet | Suna Jung Sneha Shah Geongoo Han Joel D Richter |
| author_sort | Suna Jung |
| collection | DOAJ |
| description | Fragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This redistribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing disruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS postmortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells. |
| first_indexed | 2024-03-08T19:58:36Z |
| format | Article |
| id | doaj.art-d559a06034654e76a7ae189825f49e1a |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-03-08T19:58:36Z |
| publishDate | 2023-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-d559a06034654e76a7ae189825f49e1a2023-12-24T05:31:22ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-12-012112e300241710.1371/journal.pbio.3002417FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm.Suna JungSneha ShahGeongoo HanJoel D RichterFragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This redistribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing disruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS postmortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002417&type=printable |
| spellingShingle | Suna Jung Sneha Shah Geongoo Han Joel D Richter FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm. PLoS Biology |
| title | FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm. |
| title_full | FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm. |
| title_fullStr | FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm. |
| title_full_unstemmed | FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm. |
| title_short | FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm. |
| title_sort | fmrp deficiency leads to multifactorial dysregulation of splicing and mislocalization of mbnl1 to the cytoplasm |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002417&type=printable |
| work_keys_str_mv | AT sunajung fmrpdeficiencyleadstomultifactorialdysregulationofsplicingandmislocalizationofmbnl1tothecytoplasm AT snehashah fmrpdeficiencyleadstomultifactorialdysregulationofsplicingandmislocalizationofmbnl1tothecytoplasm AT geongoohan fmrpdeficiencyleadstomultifactorialdysregulationofsplicingandmislocalizationofmbnl1tothecytoplasm AT joeldrichter fmrpdeficiencyleadstomultifactorialdysregulationofsplicingandmislocalizationofmbnl1tothecytoplasm |