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Ephrin Bs essential components of the Reelin pathway

5 April 2011. Coordinated migration of neurons in the developing and adult brain is essential for normal brain function. The secreted glycoprotein Reelin guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2 or LRP8). Loss of Reelin function in humans results in the severe developmental disorder lissencephaly and has 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.

The latest results of the research group of CEF investigator Amparo Acker-Palmer at Frankfurt University show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. The team show that ephrin Bs genetically interact with Reelin. Their results, published in the journal Nature online on 25 January 2011, demonstrate that compound mouse mutants (Reln+/−; Efnb3−/− or Reln+/−; Efnb2−/−) and triple ephrin B1, B2, B3 knockouts have neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. The Frankfurt scientists show that, mechanistically, Reelin binds to the extracellular domain of ephrin Bs, which associates 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. Activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein.

Together, these results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system.

Full paper:
A. Sentürk, S. Pfennig, A. Weiss, K. Burg & A. Acker-Palmer. 2011. Nature, doi:10.1038/nature09874; online publication 3 April 2011



Amparo Acker-Palmer
Frankfurt Institute for Molecular Live Sciences
Goethe University Frankfurt
Frankfurt am Main

e-mail: Acker-Palmer@bio.uni-frankfurt.de
tel.: +49 (069) 79829601