The role of miR17-92 in regulating thymus fate during development

Abstract

Abstract The thymus develops bilaterally from third pharyngeal pouch (3rd pp) endoderm, which is initially patterned into separate thymus and parathyroid specific domains. The transcription factors FOXN1 and GCM2 are expressed in 3rd pp thymus-fated or parathyroid-fated domains, respectively. They are required for organ development, but do not specify organ fate. We are investigating the molecular pathways required to generate a functional thymus from 3rd pp endodermal progenitors. We recently reported that Tbx1, which is required for parathyroid development, negatively regulates thymus development by suppressing Foxn1 expression. We are currently using gain-of-function and loss-of-function genetic models to test the hypothesis that Tbx1 expression in 3rd pp endoderm is regulated by microRNA (miR) 17-92. We find that TBX1 expression is expanded and FOXN1 expression is reduced in the 3rd pp endoderm of miR17-92nullembryos and that thymus organogenesis is severely impaired. We are currently targeting deletion of floxed miR17-92 to the endoderm using Sox17Cre to determine if the null phenotype is endoderm intrinsic. Similarly, Sox17Cre is being used to activate an R26miR17-92OE allele to determine the consequences of overexpressing miR17-92 in the 3rd pp endoderm. These studies will clarify the role of miR17-92 in regulating Tbx1 expression and provide insight into molecular mechanisms that regulate 3rd pp patterning and thymus organogenesis.