Sprouty genes: regulators of organogenesis and putative modifiers of 22q11 deletion (DiGeorge) syndrome

We want to determine the role of Sprouty genes in the development of the thymus and other organs affected in 22q11 deletion (DiGeorge) syndrome.

More than 1 in 4000 human babies are born with DiGeorge syndrome where a small deletion in their DNA causes defects in the development of organs such as the thymus, parathyroid, heart and middle ear. Studies in genetically altered mouse embryos have helped identify the most important gene within the 22q11 deletion as Tbx1. However, the severity of symptoms can vary greatly, suggesting that other genes outside the deleted region also play important roles.

Our recent studies on mouse embryos have suggested that the Sprouty genes control the development of many of the organs affected in DiGeorge syndrome. Using sophisticated mouse genetics we will remove the Sprouty genes from defined tissues to understand their roles during organ development. We will test whether changing the levels of Sprouty genes can affect the severity of defects in mouse models of this syndrome, which would indicate that mutations in Sprouty genes could also affect human patients in a similar way.

The pharyngeal apparatus (PA) is a transient embryonic structure from which many important organs and tissues such as the thymus, middle ear and large thoracic blood vessels are derived. The mechanisms underlying organogenesis in the PA are poorly understood due to the involvement of multiple cell types and signalling pathways. Many clinically important human syndromes are associated with defects in structures derived from the PA and understanding the genetic and developmental mechanisms that control PA development and organogenesis, should provide insights into the causes of the congenital defects associated with these syndromes. 22q11 deletion (DiGeorge or velo-cardio-facial syndrome) is the most common microdeletion syndrome in humans that occurs in 1/4000 newborn babies. Although most of these patients carry the same 1.5-3MB deletion, they exhibit much clinical variability, suggesting that the congenital defects may be caused by multigenic changes affecting one or more common signalling pathways. Recent studies have suggested key roles for two cell types, the neural crest and pharyngeal endoderm, in PA development. I propose that the Sprouty genes, which encode negative regulators of Fibroblast Growth Factor (FGF) signalling, play important roles in these cell types during PA development. We have recently produced conditional Sprouty gene knockout mice that exhibit major defects in a subset of the organs affected in DGS. We will determine the nature and incidence of these defects and tissue-specific gene deletion experiments should provide insights as to the role of the neural crest and endoderm in the development of these organs. We will analyse the molecular processes involved in regionalization of the 3rd pharyngeal pouch into thymus and parathyroid domains and the growth and separation of the thymus anlage from the pharynx. I have observed marked changes in the expression of Tbx1, one of the genes located within the 3MB 22q11 deletion, in Sprouty gene knockout embryos. I propose experiments to determine whether these changes occur as a direct consequence of alterations in the FGF signaling pathway. Finally, we will test whether Tbx1 and Sprouty genes genetically interact during PA development, which would provide direct evidence that Sprouty genes can act as genetic modifiers of some of the congenital defects associated with 22q11 deletions.