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Reelin in neuronal migration It has long been known that the secreted factor Reelin is crucial for proper neuronal migration during the development of the cortex. However, the mechanistic actions leading to a Reelin response are less well known. Acker-Palmer and colleagues reveal that the axonal guidance cue ephrin B2 acts as a co-factor with Reelin receptors to initiate signalling cascades important to produce the proper lamination of the cortex. This additional role for ephrin B2 expands the functions for this developmental protein beyond proper axonal targeting to cell migration. 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).sup.1. Loss of Reelin function in humans results in the severe developmental disorder lissencephaly.sup.2 and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer's disease.sup.3. 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.sup.+/-; Efnb3.sup.-/- or Reln.sup.+/-; Efnb2.sup.-/-) 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., Author(s): Aycan Sentürk [sup.1] , Sylvia Pfennig [sup.1] , Alexander Weiss [sup.1] [sup.2] , Katja Burk [sup.1] [sup.2] , Amparo Acker-Palmer [sup.1] Author Affiliations: (1) Frankfurt Institute for Molecular Life [...]

The formation and guidance of specialized endothelial tip cells is essential for both developmental and pathological angiogenesis (1). Notch-1 signalling regulates the generation of tip cells, which respond to gradients of vascular endothelial growth factor (VEGF-A) (2). The molecular cues and signalling pathways that control the guidance of tip cells are poorly understood. Bidirectional signalling by Eph receptors and ephrin ligands represents one of the most important guidance cues involved in axon path finding (3). Here we show that ephrin-B2 reverse signalling involving PDZ interactions regulates endothelial tip cell guidance to control angiogenic sprouting and branching in physiological and pathological angiogenesis. In vivo, ephrin-B2 PDZ-signalling-deficient mice (ephrin-B2ΔV) exhibit a reduced number of tip cells with fewer filopodial extensions at the vascular front in the mouse retina. In pathological settings, impaired PDZ signalling decreases tumour vascularization and growth. Mechanistically, we show that ephrin-B2 controls VEGF receptor (VEGFR)-2 internalization and signalling. Importantly, internalization of VEGFR2 is necessary for activation and downstream signalling of the receptor and is required for VEGF-induced tip cell filopodial extension. Together, our results suggest that ephrin-B2 at the tip cell filopodia regulates the proper spatial activation of VEGFR2 endocytosis and signalling to direct filopodial extension. Blocking ephrin-B2 reverse signalling may be an attractive alternative or combinatorial anti-angiogenic therapy strategy to disrupt VEGFR2 function in tumour angiogenesis., Vessels and nerves possess similar specialized structures--tip cells and growth cones--that, through filopodial extensions, sense the surrounding tissue for specific cues that direct their movements. Emerging evidence suggests that axonal [...]

Author(s): A. Sentrk [1]; S. Pfennig [1]; A. Weiss [1]; K. Burk [1]; A. Acker-Palmer (corresponding author) [1] replying to T. Pohlkamp et al . Nature 539, http://dx.doi.org/10.1038/nature20129 (2016). In [...]