Characterizing the physiologic roles of TRAF6 using TRAF6-deficient mice

grantor: University of TorontoThe ability of cells to respond and adapt to changes in the environment is contingent on the delivery of messages initiated at cell surface receptors to the nucleus, where appropriate genes can be switched on or off. The tumor necrosis factor receptor (TNFR) superfamily consists of a growing number of cell surface receptors that mediate diverse physiological functions with the help of intracellular adapter proteins called TNFR-associated factors (TRAFs). The six mammalian members of the TRAF family share conserved carboxy-terminal domains and, excluding TRAF1, contain amino-terminal ring finger domains thought to be pivotal for downstream signaling. Heretofore, little was known of the roles of TRAF6 'in vivo'. To determine the physiological roles of TRAF6, I generated TRAF6-deficient mice. The findings, presented in Chapter 2, provide evidence that TRAF6 is important in multiple pathways. Firstly, TRAF6 is critical in interleukin-1 (IL-1), CD40 and lipopolysaccharide (LPS) signaling. Secondly, TRAF6-deficient mice are osteopetrotic due to impaired osteoclast function. Thirdly, TRAF6 is essential in perinatal and postnatal survival. In chapter 3, the role of TRAF6 in perinatal survival was addressed by examining TRAF6-deficient embryos. Evidence is provided that deletion of TRAF6 results in exencephaly, failure of neural tube fusion and site-specific aberrations in programmed cell death (PCD) within the developing CNS. This work solidifies the 'in vivo' roles of TRAF6 as a key regulator in inflammatory pathways, cytokine signaling, bone metabolism, postnatal survival, neural tube fusion and PCD during development and provides a solid foundation for future studies regarding the as yet uncharacterized roles of TRAF6.Ph.D