The Eph subfamily of receptor tyrosine kinases mediates multiple aspects of neural development, including long-range axonal pathfinding, synaptogenesis, and synaptic plasticity. In addition, a disruption of Eph function has been linked to neurological disorders such as autism and Alzheimer's disease. In preliminary studies we identified a ligand-independent EphB signaling mechanism whereby the guanine nucleotide exchange factor Ephexin5 associates with the cytoplasmic domain of EphBs and suppresses excitatory synapse development through activation of the small GTPase RhoA. This brake on excitatory synapse development is relieved by binding of EphBs to their ephrinB ligands, which triggers rapid Ephexin5 tyrosine phosphorylation, ubiquitination, and degradation. Knockout studies in mice indicate that EphB-Ephexin5 signaling functions as a synaptogenesis checkpoint so that excitatory synapses form at the right time and place and in correct numbers during brain development. Ephexin5 loss-of-function mutations have been detected in several cases of idiopathic infantile epilepsy. We have also identified Ephexin5 as a novel neuronal substrate of the E3 ubiquitin ligase Ube3a. Loss-of-function mutations in UBE3A give rise to Angelman syndrome (AS), a neurodevelopmental disorder characterized by motor dysfunction, severe mental retardation, speech impairment, and seizures;and our preliminary findings suggest that elevated levels of Ephexin5 contribute to at least some aspects of the neurological and cognitive dysfunction associated with AS. In this proposal we address specific gaps in our understanding of the importance of the EphB-Ephexin5 complex in nervous system development and disease.
Our specific aims are: (1) to investigate the mechanisms by which EphB- Ephexin5 signaling controls synapse development, (2) to investigate the contribution of Ephexin5 mutations to human infantile epilepsy, and (3) to determine the contribution of elevated Ephexin5 levels to phenotypic defects observed in a mouse model of AS. It is our hope that the proposed experiments will advance our understanding of the molecular mechanisms controlling synapse development and ultimately provide new opportunities for the development of therapeutic strategies to combat neurodevelopmental disorders such as infantile epilepsy and autism.
Receptor tyrosine kinases are proteins of critical importance to neural development and disease. This proposal seeks to advance our understanding of the role the EphB receptor tyrosine kinase subfamily in nervous system development and the onset of various human neurological disorders.
|Robichaux, Michael A; Chenaux, George; Ho, Hsin-Yi Henry et al. (2014) EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding. Proc Natl Acad Sci U S A 111:2188-93|
|Veeramah, Krishna R; Johnstone, Laurel; Karafet, Tatiana M et al. (2013) Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54:1270-81|
|Ho, Hsin-Yi Henry; Susman, Michael W; Bikoff, Jay B et al. (2012) Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci U S A 109:4044-51|
|Wills, Zachary P; Mandel-Brehm, Caleigh; Mardinly, Alan R et al. (2012) The nogo receptor family restricts synapse number in the developing hippocampus. Neuron 73:466-81|
|Margolis, Seth S; Salogiannis, John; Lipton, David M et al. (2010) EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 143:442-55|
|Siegel, Gabriele; Obernosterer, Gregor; Fiore, Roberto et al. (2009) A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 11:705-16|
|Fu, Wing-Yu; Chen, Yu; Sahin, Mustafa et al. (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67-76|
|Paradis, Suzanne; Harrar, Dana B; Lin, Yingxi et al. (2007) An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development. Neuron 53:217-32|
|Zhou, Pengcheng; Porcionatto, Marimelia; Pilapil, Mariecel et al. (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68|
|Tolias, Kimberley F; Bikoff, Jay B; Kane, Christina G et al. (2007) The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci U S A 104:7265-70|
Showing the most recent 10 out of 11 publications