Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome

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 and Stanislav S. Zakharenko ()
Additional contact information
Tae-Yeon Eom: St. Jude Children’s Research Hospital
J. Eric Schmitt: Hospital of the University of Pennsylvania
Yiran Li: St. Jude Children’s Research Hospital
Christopher M. Davenport: St. Jude Children’s Research Hospital
Jeffrey Steinberg: St. Jude Children’s Research Hospital
Audrey Bonnan: Max Planck Florida Institute for Neuroscience
Shahinur Alam: St. Jude Children’s Research Hospital
Young Sang Ryu: St. Jude Children’s Research Hospital
Leena Paul: St. Jude Children’s Research Hospital
Baranda S. Hansen: St. Jude Children’s Research Hospital
Khaled Khairy: St. Jude Children’s Research Hospital
Stephane Pelletier: Indiana University School of Medicine
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
David R. Roalf: University of Pennsylvania
Raquel E. Gur: University of Pennsylvania
Beverly S. Emanuel: University of Pennsylvania
Donna M. McDonald-McGinn: University of Pennsylvania
Jesse N. Smith: St. Jude Children’s Research Hospital
Cai Li: St. Jude Children’s Research Hospital
Jason M. Christie: Max Planck Florida Institute for Neuroscience
Paul A. Northcott: St. Jude Children’s Research Hospital
Stanislav S. Zakharenko: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54837-3

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