David A Sassoon, PhD

\r\n\r\nThe overall interest of our research is to elucidate the cellular and molecular mechanisms that control patterning during embryogenesis in vertebrates. It is anticipated that the understanding of normal developmental mechanisms controlling cell growth and differentiation will have a strong bearing upon our understanding of cancer where normal regulatory control is lost or missregulated. \r\n

1] We have recently reported the cloning and characterization of a large multidomain Zn-finger protein called Pw1. This was a result of an effort to identify early regulators of the mesodermal/skeletal muscle lineage in murine development. PW1 is a nuclear protein expressed at high levels in muscle, liver, CNS (and pituitary) and the immune system. Differential display for myc/ p53 induced apoptosis identified a fragment of 500bp with perfect identity to Pw1. Pw1/cmyc co-expression results in apoptosis in fibroblasts, thus PW1 may be a downstream target (direct or indirect) of p53. We have recently observed that PW1 associates with tumor-necrosis-factor associated factor 2 (TRAF2). This gene is a key transducer in several cytokine pathways that lead to NFkB activation which has been recently demonstrated to inhibit cell death. Thus, PW1 appears to play a role in both cell death and cell survival. We see that PW1 is required for TRAF2 activation of NFkB. We are currently exploring its role during mouse embryogenesis and during cell differentiation. \r\n

2] We have been pursuing the role of the Wnt family of growth factors on the development of the female reproductive tract. Studies using heterografting techniques reveal that Wnt gene expression governs the proper patterning of the uterus and underlies the epithelial-mesenchymal interactions that lead to correct smooth muscle formation. Recent observations suggest that the DES syndrome in women is due to a misregulation of Wnt-7a. This misregulation ultimately leads to tumorigenesis in the reproductive tract. \r\n\r\n

3] Engrailed-2 is a homeogene expressed in the CNS and in the muscles of the jaw. We are examining what role En-2 plays in this skeletal muscle and how the expression of En-2 is specifically directed to one muscle. By generating mice that have ectopic muscle expression of En-2 and mice carrying defined regions of the EN-2 regulatory elements, we hope to provide a general picture as to how patterning is achieved during skeletal myogenesis. \r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n