Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome
Abstract Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54837-3 |
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| author | Tae-Yeon Eom J. Eric Schmitt Yiran Li Christopher M. Davenport Jeffrey Steinberg Audrey Bonnan Shahinur Alam Young Sang Ryu Leena Paul Baranda S. Hansen Khaled Khairy Stephane Pelletier Shondra M. Pruett-Miller David R. Roalf Raquel E. Gur Beverly S. Emanuel Donna M. McDonald-McGinn Jesse N. Smith Cai Li Jason M. Christie Paul A. Northcott Stanislav S. Zakharenko |
| author_facet | Tae-Yeon Eom J. Eric Schmitt Yiran Li Christopher M. Davenport Jeffrey Steinberg Audrey Bonnan Shahinur Alam Young Sang Ryu Leena Paul Baranda S. Hansen Khaled Khairy Stephane Pelletier Shondra M. Pruett-Miller David R. Roalf Raquel E. Gur Beverly S. Emanuel Donna M. McDonald-McGinn Jesse N. Smith Cai Li Jason M. Christie Paul A. Northcott Stanislav S. Zakharenko |
| author_sort | Tae-Yeon Eom |
| collection | DOAJ |
| description | Abstract Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1 +/– mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies. |
| format | Article |
| id | doaj-art-17fb65dc25454794b98e473b3b8f562c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-17fb65dc25454794b98e473b3b8f562c2024-12-08T12:36:44ZengNature PortfolioNature Communications2041-17232024-12-0115112110.1038/s41467-024-54837-3Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndromeTae-Yeon Eom0J. Eric Schmitt1Yiran Li2Christopher M. Davenport3Jeffrey Steinberg4Audrey Bonnan5Shahinur Alam6Young Sang Ryu7Leena Paul8Baranda S. Hansen9Khaled Khairy10Stephane Pelletier11Shondra M. Pruett-Miller12David R. Roalf13Raquel E. Gur14Beverly S. Emanuel15Donna M. McDonald-McGinn16Jesse N. Smith17Cai Li18Jason M. Christie19Paul A. Northcott20Stanislav S. Zakharenko21Department of Developmental Neurobiology, St. Jude Children’s Research HospitalDivision of Neuroradiology, Department of Radiology, Hospital of the University of PennsylvaniaDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalCenter for In Vivo Imaging and Therapeutics, St. Jude Children’s Research HospitalMax Planck Florida Institute for NeuroscienceDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalCenter for In Vivo Imaging and Therapeutics, St. Jude Children’s Research HospitalDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalCenter for Advanced Genome Engineering, St. Jude Children’s Research HospitalDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalDepartment of Medical and Molecular Genetics, Indiana University School of MedicineCenter for Advanced Genome Engineering, St. Jude Children’s Research HospitalBrain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, University of PennsylvaniaBrain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, University of PennsylvaniaDepartment of Pediatrics, Perelman School of Medicine, University of PennsylvaniaDepartment of Pediatrics, Perelman School of Medicine, University of PennsylvaniaDepartment of Biostatistics, St. Jude Children’s Research HospitalDepartment of Biostatistics, St. Jude Children’s Research HospitalMax Planck Florida Institute for NeuroscienceDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalAbstract Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1 +/– mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.https://doi.org/10.1038/s41467-024-54837-3 |
| spellingShingle | Tae-Yeon Eom J. Eric Schmitt Yiran Li Christopher M. Davenport Jeffrey Steinberg Audrey Bonnan Shahinur Alam Young Sang Ryu Leena Paul Baranda S. Hansen Khaled Khairy Stephane Pelletier Shondra M. Pruett-Miller David R. Roalf Raquel E. Gur Beverly S. Emanuel Donna M. McDonald-McGinn Jesse N. Smith Cai Li Jason M. Christie Paul A. Northcott Stanislav S. Zakharenko Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome Nature Communications |
| title | Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome |
| title_full | Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome |
| title_fullStr | Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome |
| title_full_unstemmed | Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome |
| title_short | Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome |
| title_sort | tbx1 haploinsufficiency leads to local skull deformity paraflocculus and flocculus dysplasia and motor learning deficit in 22q11 2 deletion syndrome |
| url | https://doi.org/10.1038/s41467-024-54837-3 |
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