[초청강연] The molecular mechanisms by which Cdo/Boc regulate normal embryonic development

Cdo and Boc, which encode a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules, are expressed in a dynamic pattern during mouse development, regulated both temporally and spatially with the highest levels in developing central nervous system, craniofacial structures and skeletal muscles. The temporal onset and restricted pattern of Cdo and Boc expression suggests that it plays a role in the determination and differentiation of cells in these tissues. Consistent with this hypothesis, Cdo knockout mice display defects in muscle and brain development, including holoprosencephaly and hydrocephalus. A major mechanism by which Cdo regulates early brain development is as a component of the Sonic Hedgehog (Shh) signaling pathway. Cdo functions in this pathway both at the signal reception, binding directly to Shh, and via a parallel pathway required at the level of Shh-dependent Gli transcription factors.A second major mechanism by which Cdo may regulate embryonic development has been revealed through mechanistic studies with skeletal myogenesis as a model system. Cdo promotes myogenic differentiation in vivo and in vitro as a component of multiprotein cell surface complexes that include the closely related protein Boc; the adhesion molecules N- and M-cadherin; and the Ig superfamily receptor Neogenin and its ligand netrin-3. Multiple signals emanate form such complexes, including the Cdo-dependent activation of the p38MAPK via direct binding of the Cdo cytoplasmic tail to a p38 scaffold protein, JLP and a Cdc42 binding protein, Bnip-2. Such signals positively regulate the activity of myogenic basic helix-loop-helix (bHLH) transcription factors, such as MyoD, at least in part via the phosphorylation of the ubiquitously expressed E-protein binding partners of the myogenic bHLH factors. The mechanism can be generalized to any tissue-specific bHLH factor, and recent work suggests that proneural bHLH factors (e.g., neurogenin1) are similarly activated by Cdo-dependent signaling.The fact that Cdo/Boc regulate the activity of bHLH factors and independently, the Shh pathway suggests it could play a dual role in neural and muscle stem cells, initially in Shh-mediated proliferation and subsequently in commitment to specific cell fates and differentiation. We hypothesize that there is a switch in Cdo/Boc function at the time of fate commitment from a pro-proliferative role to a pro-differentiation role.