Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities
Myotonic dystrophy (Dystrophia Myotonica; DM) is the most common adult-onset muscular dystrophy and its brain symptoms seriously affect patients’ quality of life. It is caused by extended (CTG)n expansions at 3′-UTR of DMPK gene (DM type 1, DM1) or (CCTG)n repeats in the intron 1 of CNBP gene (DM ty...
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| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Neuroanatomy |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnana.2019.00075/full |
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| author | Kuang-Yung Lee Kuang-Yung Lee Ho-Ching Chang Carol Seah Li-Jen Lee Li-Jen Lee Li-Jen Lee |
| author_facet | Kuang-Yung Lee Kuang-Yung Lee Ho-Ching Chang Carol Seah Li-Jen Lee Li-Jen Lee Li-Jen Lee |
| author_sort | Kuang-Yung Lee |
| collection | DOAJ |
| description | Myotonic dystrophy (Dystrophia Myotonica; DM) is the most common adult-onset muscular dystrophy and its brain symptoms seriously affect patients’ quality of life. It is caused by extended (CTG)n expansions at 3′-UTR of DMPK gene (DM type 1, DM1) or (CCTG)n repeats in the intron 1 of CNBP gene (DM type 2, DM2) and the sequestration of Muscleblind-like (MBNL) family proteins by transcribed (CUG)n RNA hairpin is the main pathogenic mechanism for DM. The MBNL proteins are splicing factors regulating posttranscriptional RNA during development. Previously, Mbnl knockout (KO) mouse lines showed molecular and phenotypic evidence that recapitulate DM brains, however, detailed morphological study has not yet been accomplished. In our studies, control (Mbnl1+/+; Mbnl2cond/cond; Nestin-Cre−/−), Mbnl2 conditional KO (2KO, Mbnl1+/+; Mbnl2cond/cond; Nestin-Cre+/−) and Mbnl1/2 double KO (DKO, Mbnl1ΔE3/ΔE3; Mbnl2cond/cond; Nestin-Cre+/−) mice were generated by crossing three individual lines. Immunohistochemistry for evaluating density and distribution of cortical neurons; Golgi staining for depicting the dendrites/dendritic spines; and electron microscopy for analyzing postsynaptic ultrastructure were performed. We found distributional defects in cortical neurons, reduction in dendritic complexity, immature dendritic spines and alterations of postsynaptic densities (PSDs) in the mutants. In conclusion, loss of function of Mbnl1/2 caused fundamental defects affecting neuronal distribution, dendritic morphology and postsynaptic architectures that are reminiscent of predominantly immature and fetal phenotypes in DM patients. |
| first_indexed | 2024-12-21T08:58:58Z |
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| issn | 1662-5129 |
| language | English |
| last_indexed | 2024-12-21T08:58:58Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroanatomy |
| spelling | doaj.art-ea7c17262efa4af1a4b11b0c34b621202022-12-21T19:09:31ZengFrontiers Media S.A.Frontiers in Neuroanatomy1662-51292019-07-011310.3389/fnana.2019.00075468933Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic DensitiesKuang-Yung Lee0Kuang-Yung Lee1Ho-Ching Chang2Carol Seah3Li-Jen Lee4Li-Jen Lee5Li-Jen Lee6Department of Neurology, Chang Gung Memorial Hospital, Keelung, TaiwanCollege of Medicine, Chang Gung University, Taoyuan, TaiwanGraduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital, Keelung, TaiwanGraduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, TaiwanInstitute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, TaiwanNeurobiology and Cognitive Science Center, National Taiwan University, Taipei, TaiwanMyotonic dystrophy (Dystrophia Myotonica; DM) is the most common adult-onset muscular dystrophy and its brain symptoms seriously affect patients’ quality of life. It is caused by extended (CTG)n expansions at 3′-UTR of DMPK gene (DM type 1, DM1) or (CCTG)n repeats in the intron 1 of CNBP gene (DM type 2, DM2) and the sequestration of Muscleblind-like (MBNL) family proteins by transcribed (CUG)n RNA hairpin is the main pathogenic mechanism for DM. The MBNL proteins are splicing factors regulating posttranscriptional RNA during development. Previously, Mbnl knockout (KO) mouse lines showed molecular and phenotypic evidence that recapitulate DM brains, however, detailed morphological study has not yet been accomplished. In our studies, control (Mbnl1+/+; Mbnl2cond/cond; Nestin-Cre−/−), Mbnl2 conditional KO (2KO, Mbnl1+/+; Mbnl2cond/cond; Nestin-Cre+/−) and Mbnl1/2 double KO (DKO, Mbnl1ΔE3/ΔE3; Mbnl2cond/cond; Nestin-Cre+/−) mice were generated by crossing three individual lines. Immunohistochemistry for evaluating density and distribution of cortical neurons; Golgi staining for depicting the dendrites/dendritic spines; and electron microscopy for analyzing postsynaptic ultrastructure were performed. We found distributional defects in cortical neurons, reduction in dendritic complexity, immature dendritic spines and alterations of postsynaptic densities (PSDs) in the mutants. In conclusion, loss of function of Mbnl1/2 caused fundamental defects affecting neuronal distribution, dendritic morphology and postsynaptic architectures that are reminiscent of predominantly immature and fetal phenotypes in DM patients.https://www.frontiersin.org/article/10.3389/fnana.2019.00075/fullmuscleblind-like knockoutsmyotonic dystrophycortical neuronsinterneuronsdendritespostsynaptic densities |
| spellingShingle | Kuang-Yung Lee Kuang-Yung Lee Ho-Ching Chang Carol Seah Li-Jen Lee Li-Jen Lee Li-Jen Lee Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities Frontiers in Neuroanatomy muscleblind-like knockouts myotonic dystrophy cortical neurons interneurons dendrites postsynaptic densities |
| title | Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities |
| title_full | Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities |
| title_fullStr | Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities |
| title_full_unstemmed | Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities |
| title_short | Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities |
| title_sort | deprivation of muscleblind like proteins causes deficits in cortical neuron distribution and morphological changes in dendritic spines and postsynaptic densities |
| topic | muscleblind-like knockouts myotonic dystrophy cortical neurons interneurons dendrites postsynaptic densities |
| url | https://www.frontiersin.org/article/10.3389/fnana.2019.00075/full |
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