Eom Tae-Yeon, Schmitt J Eric, Li Yiran, Davenport Christopher M, Steinberg Jeffrey, Bonnan Audrey, Alam Shahinur, Ryu Young Sang, Paul Leena, Hansen Baranda S, Khairy Khaled, Pelletier Stephane, Pruett-Miller Shondra M, Roalf David R, Gur Raquel E, Emanuel Beverly S, McDonald-McGinn Donna M, Smith Jesse N, Li Cai, Christie Jason M, Northcott Paul A, Zakharenko Stanislav S
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2024 Dec 5;15(1):10510. doi: 10.1038/s41467-024-54837-3.
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.
神经发育障碍被认为源于大脑内在异常。或者，它们可能源于组织间串扰的破坏。在这里，我们展示了在患有22q11.2缺失综合征（22q11DS）的小鼠模型和人类中，两个前庭小脑小叶——旁绒球和绒球的局部缩小。在小鼠中，这种旁绒球/绒球发育异常与Tbx1基因单倍剂量不足有关。Tbx1单倍剂量不足还会导致小脑突触可塑性和运动学习受损。然而，发育异常的旁绒球/绒球中的神经细胞组成和神经发生并未改变。有趣的是，22q11DS小鼠和Tbx1小鼠的岩下窦窝（颞骨岩部的一部分，包裹着旁绒球/绒球）存在畸形。单核RNA测序显示，Tbx1单倍剂量不足导致颞骨岩部软骨细胞向成骨细胞的早熟分化，这独立于旁绒球/绒球细胞群体。这些发现揭示了22q11DS中一种以前未被认识到的致病结构/功能关系，即局部骨骼畸形和小脑发育异常导致行为缺陷。
