XEDAR, EDAR and TAJ are three recently isolated receptors of the TNFR family that are mainly expressed in ectodermal derivatives during embryonic development. We have characterized the signaling pathways activated by XEDAR and discovered that it binds to TRAF3 and TRAF6 in a ligand-dependent fashion and activates the NF-kappaB and JNK pathways. Although XEDAR does not possess a death domain, it also induces apoptosis via both caspase-dependent and independent mechanisms. The overall aim of this proposal is to identify the downstream genes involved in the activation of NF-kappaB, JNK and cell death pathways by XEDAR and to compare its signaling activities with those of EDAR and TAJ. We plan to achieve this goal through the following specific aims.
In specific aims 1 we will try to identify the genes involved in the activation of NF-kappaB and JNK pathways by XEDAR and its homologs.
Specific aim 2 will focus on delineating the proteins involved in induction of caspase-dependent and independent cell death via XEDAR.
In specific aim 3, we will identify novel proteins which are involved in signaling via XEDAR and its homologs. We believe that the above studies will not only lead to a better understanding of the process of ectodermal differentiation and craniofacial development but also help to clarify the clinical heterogeneity of ectodermal dysplasias. In the long-term these studies may lead to better diagnosis and treatment of ectodermal dysplasias and craniofacial abnormalities.
