This proposal focuses on the signal transduction cascades that are used to wire the nervous system. Without question the brain and spinal cord form the most complicated organ, functioning as the biological supercomputer to control everything in the body, from sensing the environment and initiating movement, to learning, memory, speech and behavior. What is most amazing is that this supercomputer self-assembles during development as each neuron sends out a thin wire-like extension, the axon, which can travel great distances to reach its target. The Eph receptors and their membrane-anchored ephrin ligands play important roles in guiding axons to their targets. In addition to axon pathfinding, Ephs and ephrins control many other cell-cell interactions, including those that occur during hindbrain segmentation and cardiovascular development. Eph receptors have a cytoplasmic protein-tyrosine kinase catalytic domain, while the B-subclass ephrins have a short cytoplasmic domain. Our previous genetic and biochemical studies were the first to demonstrate that when Eph receptor-expressing cells contact ephrin-expressing cells, both molecules become tyrosine phosphorylated and both send signals into their respective cell. Over the past five years, our hypothesis that ephrins and Eph receptors transduce bidirectional signals has become a key feature in the study of this large family of 14 receptors and 8 ephrins. In addition to ongoing biological studies of Eph/ephrin functions, we have focused on defining the biochemistry of this bidirectional cell-cell communication system to understand how these signals are transduced at the molecular level. We have identified a number of proteins that physically associate with the cytoplasmic domains of the ephrins and Eph receptors. These molecules contain important protein-protein interaction domains involved in signal transduction and subcellular localization, including Src homology 2 (SH2) domains (which bind phosphotyrosine sequences), SH3 domains (which bind poly-proline sequences) and PDZ domains (which bind the carboxy-terminus of certain proteins). By identifying and characterizing proteins that physically associate with ephrins and Eph receptors, our long-term objective is to define the signal transduction cascades and cellular responses initiated by bidirectional signaling. In addition to increasing our general knowledge about biochemical signal transduction cascades that control cell-cell interactions and axon guidance, these studies may provide insight into potential molecular targets that may be used to develop therapies of the future, such as those needed to regenerate severed connections following a spinal cord injury.
| Liu, Xian-Dong; Zhu, Xiao-Na; Halford, Michael M et al. (2018) Retrograde regulation of mossy fiber axon targeting and terminal maturation via postsynaptic Lnx1. J Cell Biol 217:4007-4024 |
| Talebian, Asghar; Britton, Rachel; Henkemeyer, Mark (2018) Abnormalities in cortical interneuron subtypes in ephrin-B mutant mice. Eur J Neurosci 48:1803-1817 |
| Talebian, Asghar; Britton, Rachel; Ammanuel, Simon et al. (2017) Autonomous and non-autonomous roles for ephrin-B in interneuron migration. Dev Biol 431:179-193 |
| Zhu, Xiao-Na; Liu, Xian-Dong; Sun, Suya et al. (2016) Ephrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour. Nat Commun 7:11096 |
| Zhu, Xiao-Na; Liu, Xian-Dong; Zhuang, Hanyi et al. (2016) Amygdala EphB2 Signaling Regulates Glutamatergic Neuron Maturation and Innate Fear. J Neurosci 36:10151-62 |
| Robichaux, Michael A; Chenaux, George; Ho, Hsin-Yi Henry et al. (2016) EphB1 and EphB2 intracellular domains regulate the formation of the corpus callosum and anterior commissure. Dev Neurobiol 76:405-20 |
| Kwak, Hyeongil; Salvucci, Ombretta; Weigert, Roberto et al. (2016) Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow. J Clin Invest 126:4554-4568 |
| Pohlkamp, Theresa; Xiao, Lei; Sultana, Rukhsana et al. (2016) Ephrin Bs and canonical Reelin signalling. Nature 539:E4-E6 |
| Zhang, Gu; Brady, John; Liang, Wei-Ching et al. (2015) EphB4 forward signalling regulates lymphatic valve development. Nat Commun 6:6625 |
| Villar-Cerviño, Verona; Kappeler, Caroline; Nóbrega-Pereira, Sandrina et al. (2015) Molecular mechanisms controlling the migration of striatal interneurons. J Neurosci 35:8718-29 |
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