Signature Gene Expression Patterns Revealed in Hypoplastic Thymii from Mouse Models of DiGeorge-22q11.2 Deletion Syndrome

Abstract

Chromosome 22q11.2 deletion syndrome (22q11.2 ΔS) is the most common microdeletion disorder reported (1/4000). Individuals with this deletion have variable, multi-system disorders including thymic hypoplasia, cardiac anomalies, hypoparathyroidism, and/or dysmorphic facial features. Over 90% of patients have a deletion of 2.4 Mb, which comprises 90 genes, 50% protein coding and the remainder microRNAs, long noncoding RNAs and pseudogenes. The principal cause of the development defects is a haploinsufficiency of the T-box 1 transcription factor (Tbx1). Between 40–60% of patients have some degree of thymic hypoplasia, resulting in systemic T cell lymphopenia. Defects in the thymic stromal tissue is the underlying cause of the hypoplasia. We analyzed the thymic tissue in the mouse models of 22q11.2 ΔS (Df1/+). Comparative transcriptome analyses of hypoplastic and normal-sized lobes derived from the same Df1/+ embryo revealed a signature mRNA expression pattern unique to hypoplastic lobes. Ingenuity pathway analysis uncovered selective pathways compromised in the hypoplastic lobes. Fetal thymic organ culture and reaggregate cultures are currently being used to identify the genes essential for the specification and expansion of the thymic stroma. In addition, normal and hypoplastic thymii, including some from 22q11.2 ΔS patients, are being characterized for the expression of the over- and under-represented genes identified in the mouse model. Findings from these studies may lead to better strategies for improving human thymopoiesis in patients with conditions including 22q11.2 and 10p syndromes, those undergoing chemoablative treatments, and other conditions leading to a thymic hypoplasia and ensuing T cell lymphopenia.