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Nat. Commun., 05 December 2024;15;10510 | https://doi.org/10.1038/s41467-024-54837-3
Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome
Tae-Yeon Eom1, J. Eric Schmitt2,3, Yiran Li1, Christopher M. Davenport1, Jeffrey Steinberg4, Audrey Bonnan5, Shahinur Alam1,6, Young Sang Ryu4, Leena Paul1, Baranda S. Hansen7, Khaled Khairy1,6, Stephane Pelletier8, Shondra M. Pruett-Miller7,9, David R. Roalf3, Raquel E. Gur3, Beverly S. Emanuel10,11, Donna M. McDonald-McGinn10,11,12, Jesse N. Smith13, Cai Li13, Jason M. Christie5,14, Paul A. Northcott1 & Stanislav S. Zakharenko1
1Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
2Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
3Brain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
4Center for In Vivo Imaging and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
5Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA.
6Center for Bioimage Informatics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
7Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
8Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
9Department of Cell & Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
10Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
11Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
12Department of Molecular Medicine, Division of Human Biology and Medical Genetics, Sapienza University, Rome 00185, Italy.
13Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
14Department of Physiology and Biophysics, University of Colorado Anschutz School of Medicine, Aurora, CO 80045, USA.
Corresponding author
Correspondence to Stanislav S. Zakharenko.
1Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
2Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
3Brain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
4Center for In Vivo Imaging and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
5Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA.
6Center for Bioimage Informatics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
7Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
8Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
9Department of Cell & Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
10Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
11Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
12Department of Molecular Medicine, Division of Human Biology and Medical Genetics, Sapienza University, Rome 00185, Italy.
13Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
14Department of Physiology and Biophysics, University of Colorado Anschutz School of Medicine, Aurora, CO 80045, USA.
Corresponding author
Correspondence to Stanislav S. Zakharenko.
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.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2024-12-09)
- 국외 연구진
- 생명과학 > 신경생물학
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