Characterization of the Thymic Hypoplasia in Mouse Models of 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Abstract

Abstract Patients with 22q11.2 deletion syndrome have variable, multi-system disorders including a thymic hypoplasia, cardiac anomalies, and hypoparathyroidism. Over 90% have a deletion of 2.5 Mb on chromosome 22q11.2, affecting protein coding genes, microRNAs, long noncoding RNAs, and pseudogenes. 50%~70% have some degree of thymic hypoplasia (DiGeorge syndrome), resulting in a T cell lymphopenia. Successful transplantation of thymic tissue in patients with a thymic aplasia suggests stromal tissue abnormalities. The thymic stroma consists of thymic epithelial cells (TEC), mesenchymal cells, and endothelial populations. We are exploring the TEC-mesenchyme-endothelial interactions during thymus organogenesis in the mouse model of 22q11.2 deletion syndrome (Df1/+). Comparative transcriptome analyses of hypoplastic and normal thymic lobes from embryos revealed a unique mesenchymal cells mRNA expression signature, including reduced levels of the PDGFRa. PDGFRaH2B-EGFP heterozygous mice that have lower level of PDGFRa expression are being crossed with the Df1/+ model to ascertain whether the hypoplasia is influenced by this receptor. Additional mouse models with prominent penetrance of thymic hypoplasia are being used to determine how Tbx1 (encoded on 22q11.2) influences pharyngeal pouch mesenchymal-TEC development. The results from the study will likely lead to novel approaches for thymus reconstitution in various clinical settings.