Proteolytic cleavage of transmembrane cell adhesion molecule L1 by extracellular matrix molecule Reelin is important for mouse brain development

TY - JOUR

T1 - Proteolytic cleavage of transmembrane cell adhesion molecule L1 by extracellular matrix molecule Reelin is important for mouse brain development

AU - Lutz, David

AU - Sharaf, Ahmed

AU - Drexler, Dagmar

AU - Kataria, Hardeep

AU - Wolters-Eisfeld, Gerrit

AU - Brunne, Bianka

AU - Kleene, Ralf

AU - Loers, Gabriele

AU - Frotscher, Michael

AU - Schachner, Melitta

PY - 2017/11/10

Y1 - 2017/11/10

N2 - The cell adhesion molecule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80). Expression of N-R6 and generation of L1-80 coincide in time at early developmental stages of the cerebral cortex. Reelin-mediated generation of L1-80 is involved in neurite outgrowth and in stimulation of migration of cultured cortical and cerebellar neurons. Morphological abnormalities in layer formation of the cerebral cortex of L1-deficient mice partially overlap with those of Reelin-deficient reeler mice. In utero electroporation of L1-80 into reeler embryos normalised the migration of cortical neurons in reeler embryos. The combined results indicate that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1-80 contribute to brain development at early developmental stages.

AB - The cell adhesion molecule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80). Expression of N-R6 and generation of L1-80 coincide in time at early developmental stages of the cerebral cortex. Reelin-mediated generation of L1-80 is involved in neurite outgrowth and in stimulation of migration of cultured cortical and cerebellar neurons. Morphological abnormalities in layer formation of the cerebral cortex of L1-deficient mice partially overlap with those of Reelin-deficient reeler mice. In utero electroporation of L1-80 into reeler embryos normalised the migration of cortical neurons in reeler embryos. The combined results indicate that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1-80 contribute to brain development at early developmental stages.

KW - Animals

KW - Cell Adhesion Molecules, Neuronal/genetics

KW - Cell Movement/physiology

KW - Cerebral Cortex/cytology

KW - Extracellular Matrix Proteins/genetics

KW - Mice

KW - Mice, Knockout

KW - Nerve Tissue Proteins/genetics

KW - Neural Cell Adhesion Molecule L1/genetics

KW - Neurons/cytology

KW - Proteolysis

KW - Serine Endopeptidases/genetics

U2 - 10.1038/s41598-017-15311-x

DO - 10.1038/s41598-017-15311-x

M3 - SCORING: Journal article

C2 - 29127326

VL - 7

SP - 15268

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -