22q11.2 Deletion Syndrome Causes a Sox-9–Mediated Expansion of Chondrocytes Limiting Embryonic Thymus Growth Correctable by Minoxidil

Thymic hypoplasia, hypoparathyroidism, cardiac defects, and/or dysmorphic facial features are frequent congenital malformations resulting from chromosome 22q11.2 deletion syndrome (22q11.2DS; aka DiGeorge syndrome). Thymus hypoplasia results in reduced peripheral T cells, with patients suffering from more frequent and severe infections. Embryonic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) are smaller than controls. Such thymuses had a distinct mesenchymal cell subset representation, altered transcriptomes, and elevated levels of collagens and extracellular matrix (ECM) proteins. We report that the administration of minoxidil or PGE2 to pregnant mice restored thymic tissue growth in Tbx1neo2/neo2 embryos. The drugs normalized the embryonic thymic mesenchymal subcluster representation, their respective transcriptomes, and corrected the underdeveloped vasculature. Importantly, the restoration of thymic growth matched the reduced number of perivascular/chondrogenic-derived mesenchymal subsets. Comparative transcriptomic, gene expression, and immunofluorescence analyses revealed elevated expression levels of a trio of Sox family transcription factors (Sox5, 6, and 9) in the small thymuses. Sox9 positively regulates the expression type II, IX, and X cartilaginous collagens and other ECM proteins, which are elevated in the hypoplastic lobes. Notably, minoxidil or PGE2 treatments reduced Sox9 expression and the correspondingly regulated collagens. This treatment also corrected the location of the parathyroids, indicating that a therapeutic drug treatment can correct several congenital defects associated with 22q11.2DS.