ROBERT KRAUSS

..CDO and BOC are proposed to be components of a receptor complex that mediates some of the cell-cell interactions between muscle precursors that are required for myogenesis...

..Nevertheless, it is possible that the murine adhesion receptors rate-limiting in vivo have not yet been identified or fully assessed...

..Abl's promyogenic effect is therefore linked to a multiprotein cell surface complex that regulates differentiation-dependent p38 activation...

..Furthermore, these model systems suggest that human HPE arises from a complex interaction between the timing and strength of developmental signalling pathways, genetic variation and exposure to environmental agents...

..abstract:..

..Mechanistic studies in vitro indicate that specific cadherins and immunoglobulin superfamily proteins exert some of their effects in an interdependent fashion by signaling from a multiprotein complex found at sites of cell-cell contact...

..These results document a novel mechanism of signaling during cell differentiation: the interaction of a MAPK scaffold protein with a cell surface receptor...

..Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38alpha/beta activation during cell differentiation...

..The promyogenic effect of cell-cell contact is therefore linked to the activity of myogenic bHLH factors. Furthermore, the myogenic positive feedback network extends from the cell surface to the nucleus...

..Thus, some of the cell-cell contact-mediated activities that are required for myogenesis seem to be based on interdependent activities of promyogenic classical cadherins and Ig superfamily members...

..These observations are consistent with the notion that CDO and BOC play a role in the inverse relationship between differentiation and transformation of cells in the skeletal muscle lineage...

..It is proposed that netrin-3 and neogenin may promote myogenic differentiation by an autocrine mechanism as components of a higher order complex of several promyogenic cell surface proteins...

..Specific Cdo domains required for its promyogenic effect are dispensable for its Shh signaling role, suggesting that Cdo has multiple, independent functions...

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..Together, netrin-neogenin signaling is an important extracellular cue in regulation of myogenic differentiation and myofiber size...

..These results indicate that CDO promotes neuronal differentiation and support the hypothesis that CDO coordinates differentiation of multiple cell lineages by regulating the activity of tissue-specific bHLH factors...

..Furthermore, they are consistent with a model whereby Cdo serves as a multifunctional coreceptor with mechanistically distinct roles in multiple signaling pathways...

..Taken together, these results suggest that CD164 is a regulator of myoblast motility and that this property contributes to its ability to promote myoblast fusion into myotubes...

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..Here, we review forebrain development with an emphasis on the pathways known to be defective in HPE and describe the strengths and weaknesses of various murine models of HPE...

..Cdo and Boc bind Shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where Cdo and Boc enhance Shh signaling within its target field...

..The coordinate regulation of the activity and expression of several different positively and negatively acting Shh binding proteins should result in fine-tuned modulation of graded Shh signaling...

..Such information may have important public health impact and could ultimately aid in the counseling of HPE mutation carriers. ..

..These experiments will provide information critical to molecular and genetic understanding of CD164's role in myogenesis. This research should therefore shed light on fundamental processes by which skeletal muscles develop. ..

..This research should shed light on fundamental processes by which skeletal muscles develop and therefore advance potential strategies for improved treatment of skeletal muscle diseases. ..

..Studies on this model, and its extension to additional ethanol-associated birth defects, are proposed, with the goal of shedding light on how genetic susceptibility may influence the outcome of fetal alcohol exposure. ..

..Such genes represent potential mediators of the transformed phenotype. ..

..The proposed work will provide information critical to a molecular understanding of CDO's role in myogenesis and should therefore shed light on fundamental processes by which skeletal muscles develop. ..

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..Studies on this model, and its extension to additional ethanol-associated birth defects, are proposed, with the goal of shedding light on how genetic susceptibility may influence the outcome of fetal alcohol exposure. ..