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.

Genetics and mechanisms leading to human cortical malformations

“…Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1, which is necessary for Reelin signaling. Compound mouse mutants (Reln +/− ; Efnb3 −/− or Reln +/− ; Efnb2 −/− ) and triple ephrin B1, B2, B3 KOs show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse [165]. Loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation.…”

“…Dab1 activates additionally other signaling pathways, eg involving PI3K. Interestingly, the activation of ephrin Bs can rescue the phenotype of neuronal migration defects in reeler slices, allowing neurons to reach layers II-III [165]. Ephrin B induces the formation of a macromolecular complex required for Src recruitment/activation and Reln signaling.…”

“…Ephrin B induces the formation of a macromolecular complex required for Src recruitment/activation and Reln signaling. Sentürk and col. [165] concluded that ephrin Bs are essential components of the Reln receptor/signaling pathway controlling neuronal migration during nervous system development.…”

Reelin Induces Erk1/2 Signaling in Cortical Neurons Through a Non-canonical Pathway

“…Other studies reported Reelin binding to Cadherin-related neuronal receptor (CNR) family, particularly CNR1 (61), a finding that has been disputed by other investigators (32). Other potential non-lipoprotein Reelin receptors include ephrin B proteins and the interacting EphB transmembrane tyrosine kinases, which were reported to bind the N-terminal region of Reelin (62,63). Because CNR1, ephrin B and EphB are expressed in neurons and associate with the SFKs, they could conceivably mediate the induction of Erk1/2 signaling.…”

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

“…Ephrin-B2, member of the largest receptor tyrosine kinase family, is a bidirectional signaling molecule important in development, 1 vascularization, 2 nervous system patterning (axon guidance), 3,4 angiogenesis, 5,6 and cancer. 5 The presence of the Eph receptor on neighboring cells is a key determinant in activating the signaling cascade in the interacting ephrin-B2 expressing cells.…”