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The Journal of Neuroscience, April 18, 2007, 27(16):4243-4252; doi:10.1523/JNEUROSCI.0023-07.2007

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Development/Plasticity/Repair
Processing of Reelin by Embryonic Neurons Is Important for Function in Tissue But Not in Dissociated Cultured Neurons

Yves Jossin, Lanrun Gui, and André M. Goffinet

Developmental Neurobiology Unit, Université Catholique de Louvain, B1200 Brussels, Belgium

Correspondence should be addressed to Dr. André M. Goffinet, Developmental Neurobiology Unit, Université Catholique de Louvain, Avenue E. Mounier, 73, Box DENE 7382, B1200 Brussels, Belgium. Email: Andre.Goffinet{at}dene.ucl.ac.be

Reelin, the protein defective in reeler mutant mice, plays a key role during brain development. Reelin is processed proteolytically at two sites, and the central fragment mimics function in vitro.

Here, we show that processing is functionally important in vivo, a question that could not be addressed in our previous study. New monoclonal antibodies directed against central Reelin block its binding to lipoprotein receptors and perturb cortical development in vitro, confirming the importance of the central fragment that is detected in tissue and body fluids. Processing occurs when Reelin is incubated with embryonic neurons in culture or with their supernatant, but inhibition of processing by a metalloproteinase blocker does not prevent Reelin signaling in neurons. Furthermore, neurons internalize similarly full-length or central Reelin. In contrast, inhibition of processing prevents signaling and perturbs cortical development in cultured embryonic brain slices. Moreover, in vivo, the concentration of central Reelin is dramatically and selectively increased in receptor-deficient tissue, suggesting its specific downregulation after binding to receptors and internalization. We propose that processing by end-migration neurons is required in tissue (where Reelin is likely anchored to the extracellular matrix) to release the central fragment that diffuses locally and signals to target cells, whereas, in vitro, all Reelin forms have indiscriminate access to cells, so that cleavage is not necessary for signaling.

Key words: metalloproteinase; Dab1; VLDLR; ApoER2; monoclonal antibodies; cerebral cortex

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Received Sept. 15, 2006; revised March 2, 2007; accepted March 9, 2007.

Correspondence should be addressed to Dr. André M. Goffinet, Developmental Neurobiology Unit, Université Catholique de Louvain, Avenue E. Mounier, 73, Box DENE 7382, B1200 Brussels, Belgium. Email: Andre.Goffinet{at}dene.ucl.ac.be

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				T. Uchida, A. Baba, F. J. Perez-Martinez, T. Hibi, T. Miyata, J. M. Luque, K. Nakajima, and M. Hattori Downregulation of Functional Reelin Receptors in Projection Neurons Implies That Primary Reelin Action Occurs atEarly/Premigratory Stages J. Neurosci., August 26, 2009; 29(34): 10653 - 10662. [Abstract] [Full Text] [PDF]

				P. Chameau, D. Inta, T. Vitalis, H. Monyer, W. J. Wadman, and J. A. van Hooft The N-terminal region of reelin regulates postnatal dendritic maturation of cortical pyramidal neurons PNAS, April 28, 2009; 106(17): 7227 - 7232. [Abstract] [Full Text] [PDF]

				Y. Jossin and A. M. Goffinet Reelin Signals through Phosphatidylinositol 3-Kinase and Akt To Control Cortical Development and through mTor To Regulate Dendritic Growth Mol. Cell. Biol., October 15, 2007; 27(20): 7113 - 7124. [Abstract] [Full Text] [PDF]

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