title: Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.
abstract: Coordinated migration of neurons in the developing and adult brain is essential for its proper function. The secreted glycoprotein Reelin (also known as RELN) guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, also known as LRP8). Loss of Reelin function in humans results in the severe developmental disorder lissencephaly and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer's disease. The molecular mechanisms by which Reelin activates its receptors and controls cellular functions are largely unknown. Here we show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. We show that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln(+/-); Efnb3(-/-) or Reln(+/-); Efnb2(-/-)) and triple ephrin B1, B2, B3 knockouts show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. Mechanistically, we show that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 which is necessary for Reelin signalling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Together, our results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system.
authors: Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany.
authors: Aycan
authors: A
authors: Sentürk
authors: Sylvia
authors: S
authors: Pfennig
authors: Alexander
authors: A
authors: Weiss
authors: Katja
authors: K
authors: Burk
authors: Amparo
authors: A
authors: Acker-Palmer
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D036387:Ephrin-B1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D036388:Ephrin-B2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D036389:Ephrin-B3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D036342:Ephrins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D036387:Ephrin-B1; D036388:Ephrin-B2; D036389:Ephrin-B3; D036342:Ephrins; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases