Research of the Month

August 2018

Science. 2018 Aug 24;361(6404). pii: eaao2861. doi: 10.1126/science.aao2861

Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system

Segarra M*, Aburto MR*, Cop F*, Llaó-Cid C, Härtl R, Damm M, Bethani I, Parrilla M, Husainie D, Schänzer A, Schlierbach H, Acker T, Mohr L, Torres-Masjoan L, Ritter M, Acker-Palmer A

The brain is composed by an intricate network of neurons, glial cells and vessels that closely interact to develop a functional organ and to maintain its homeostasis. In the classical view of the corticogenesis, neurons migrate in waves along the radial glia cells to reach their final position and form a layered structure. The Acker-Palmer group has unveiled a new perspective in the development and function of the cerebral cortex by showing that the blood vessels actively contribute to this process and are essential to coordinate the communication between glial cells and neurons.

 

Reelin is a neuronal guidance cue that regulates the correct positioning of the neurons in the layered structures of the brain. Reelin binds to its receptors ApoER2 and VLDLR and activates the intracellular effector Dab1. In the absence of Reelin or Dab1, the cerebellar cortex is aberrantly laminated and these mouse mutants present several neurological defects. The group headed by Prof Acker-Palmer has found that Reelin can also signal to endothelial cells, which express ApoER2 and Dab1, and has a prominent proangiogenic function. Mechanistically, Reelin synergistically crosstalks with the VEGF pathway and both signals induce the clustering of the ApoER2 and VEGFR2 receptors which converge in the activation of Dab1, leading to endothelial cell proliferation and endothelial tip cell formation (panel A). Blood vessels vascularize the developing neural tube simultaneously as the neuronal migration process occurs. Importantly, Segarra et al. showed that vascular specific deletion of Dab1 results in misplaced neuronal positioning. These cortical lamination defects partially recapitulate ReelinKO and Dab1KO cortical phenotype. Moreover, Dab1-null vessels induce the detachment of the radial glial cell processes docking at the penetrating pial vessels of the cortex. Therefore, a vascular specific signaling mutation alters the development of the cerebral cortex, targeting both the neuronal and the glial organization, and these defects are independent from the vascular perfusion function (panel B). Furthermore, vessels are the central component of the neurovascular unit, a particular cell entity in the brain, which main function is the establishment of the blood-brain barrier (BBB). Acker-Palmer group explored whether vascular Reelin signaling was also playing a role on BBB integrity and found that vascular Dab1 molecule regulates the barriergenesis in the brain and the retina. Segarra et al. delineated that activated Dab1 promotes the secretion of the vascular-derived basal membrane protein laminina4 which sustains the attachment of the astrocytic end-foot processes via the activation of cell adhesion receptor integrinb1 in glial cells (panels B and C). The ultrastructure of the BBB was analysed in the frame of a long standing ECCPS cooperation with the laboratory of Prof. Till Acker in the Neuropathology Institute in Giessen. In sum, the ECCPS researchers discovered a novel function of the vasculature in the central nervous system development and homeostasis. Their work has an important impact towards understanding the aetiology of neurological disorders comprising vascular and neural dysfunction.



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