Recently, a study conducted by researchers from Dr. XIONG Zhiqi’s lab at the Institute of Neuroscience of Chinese Academy of Sciences described the critical role of ADAM10-initiated release of Notch intracellular domain in the radial migration of cortical neurons and provided evidence showing the function of a new membrane signal paradigm, namely regulated intramembrane proteolysis (RIP), in the regulation of cortical radial migration in mouse brain. The findings were published online in Cerebral Cortex.

Proper neuron migration is essential to brain morphogenesis and circuit formation, and dysregulation of it usually causes severe brain disorders. Regulated intramembrane proteolysis (RIP), a process in which a transmembrane protein releases its cytoplasmic domain via sequential proteolytic cleavage, has recently been implicated in the regulation of neuronal migration, but the underlying molecular mechanism remains unclear.

In this study, researchers used both in utero electroporation and tamoxifen induced-deletion to selectively inactivate ADAM10 in cortical neurons, and found that the radial migration of these neurons was disrupted. The function of ADAM10 in migration was found to be dependent on the RIP of Notch as its intracellular domain Notch intracellular domain (NICD) mitigated the migration defect of ADAM10-deficiency neurons, and ADAM10/Notch signaling was found to affect microtubule structure and neuronal motility by regulating the transcription of microtubule-associated proteins (MAPs), which is distinct from formerly identified function of Notch in proliferation and fate control.

Specifically, neuronal expression level of doublecortin (DCX), a critical modulator of microtubule dynamics, was found to be a direct target of the NICD/RBPJ transcriptional activation complex in migrating neurons. Expression of NICD prevented the down-regulation of DCX, and overexpressing DCX significantly restored the level of acetylated tubulin and mitigated the migration defect of ADAM10-deficient neurons.  

This study also revealed that ADAM10-mediated RIP functions as a new membrane signal transduction paradigm in the regulation of neuron migration. Together with paradigms such as ligand-receptor binding or interaction between adhesion molecules, ADAM10-initiated RIP of Notch enable newborn neurons with multiple strategies to sense environmental stimuli and precisely orchestrate intracellular molecular machinery for migration.

The discovery that ADAM10/Notch signaling regulates microtubule cytoskeleton dynamics to control neuronal motility provides a general, conceptual advance for how this signaling pathway is involved in these cellular processes. Anti-mitotic or microtubule compounds have been shown with promising therapeutic effect to treat leukemia, which is associated with mutations of Notch1 in human patients. The link between ADAM10-initiated RIP of Notch and microtubule cytoskeleton should help the development of new drugs for the treatment of related diseases.

Moreover, the identification of Dcx gene as a direct target of NICD/RBPJ complex provides a specific and direct mechanism underlying the requirement of ADAM10-initiated RIP of Notch in regulating neuronal migration. These findings advanced the knowledge of the molecular mechanisms underlying neuronal migration and brain development.