Tbx1 haploinsufficiency induces bone-to-cerebellar deformity in 22q11.2 deletion syndrome

ABSTRACT: 22q11.2 deletion syndrome (22q11DS) substantially increases the risk of cognitive decline and psychiatric disease. However, neuroanatomic changes in 22q11DS are of a subtle-to-moderate degree and their connection to brain function is not clear. Here we report a severe (~70%) and specific reduction (dysplasia) of two cerebellar lobules, paraflocculus and flocculus (PF/F) and associated deficits in vestibulo-ocular reflex (VOR) in mouse models of 22q11DS (22q11DS mice). A specific but less severe PF/F dysplasia was confirmed in humans with 22q11DS. Tbx1 haploinsufficiency recapitulated the PF/F and VOR deficits in 22q11DS mice. The 22q11DS-associated PF/F dysplasia was not due to altered neural composition or neurogenesis. Rather, a part of temporal bone called subarcuate fossa (SF), which encapsulates the PF/F, and semicircular canals of the inner ear, which connects to the SF were malformed in 22q11DS and Tbx1-deficientmice. Our single-nuclei RNA Sequencing and immunohistochemistry data revealed that Tbx1 haploinsufficiency caused precocious differentiation of chondrocyte to osteoblasts in the petrous bone, but no changes in cell type compositions in the PF/F. These data suggest a novel structure-function pathogenic interrelationship in 22q11DS, where Tbx1 haploinsufficiency causes a skeletal deformity occluding cerebellar development and resulting in motor learning deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE254044 | GEO | 2024/09/19

REPOSITORIES: GEO