Abstract
While Munc18–1 interacts with Syntaxin1 and controls the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex to regulate presynaptic vesicle fusion in developed neurons, this molecule is likely to be involved in brain development since its gene abnormalities cause early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome), neonatal epileptic encephalopathy and other neurodevelopmental disorders. We thus analyzed physiological significance of Munc18–1 during cortical development. Munc18–1-knockdown impaired cortical neuron positioning during mouse corticogenesis. Time-lapse imaging revealed that the mispositioning was attributable to defects in radial migration in the intermediate zone and cortical plate. Notably, Syntaxin1A was critical for radial migration downstream of Munc18–1. As for the underlying mechanism, Munc18–1-knockdown in cortical neurons hampered post-Golgi vesicle trafficking and subsequent vesicle fusion at the plasma membrane in vivo and in vitro, respectively. Notably, Syntaxin1A-silencing did not affect the post-Golgi vesicle trafficking. Taken together, Munc18–1 was suggested to regulate radial migration by modulating not only vesicle fusion at the plasma membrane to distribute various proteins on the cell surface for interaction with radial fibers, but also preceding vesicle transport from Golgi to the plasma membrane. Although knockdown experiments suggested that Syntaxin1A does not participate in the vesicle trafficking, it was supposed to regulate subsequent vesicle fusion under the control of Munc18–1. These observations may shed light on the mechanism governing radial migration of cortical neurons. Disruption of Munc18–1 function may result in the abnormal corticogenesis, leading to neurodevelopmental disorders with MUNC18–1 gene abnormalities.
Highlights
Munc18 proteins are essential regulators of exocytosis, and mammals express 3 highly homologous isoforms, Munc18–1~3
When Munc18–1 expression during mouse corticogenesis was examined by western blotting, it was detected from E13.5 and gradually increased throughout the developmental process analyzed until postnatal day (P)30 (Fig 1a)
Munc18–1 was detected moderately in the cortical plate (CP) during corticogenesis while it was barely detected in the progenitor and stem cells in the ventricular zone (VZ)/subventricular zone (SVZ) throughout the development (Fig 1b)
Summary
Munc (mammalian homologs of Caenorhabditis elegans uncoordinated-18) proteins are essential regulators of exocytosis, and mammals express 3 highly homologous isoforms, Munc18–1~3. Molecular mechanism underlying the etiology of disorders with MUNC-18-1 ( known as STXBP1) gene abnormalities remains to be elucidated, the abovementioned reports may indicate that MUNC18–1 regulates excitatory neuron positioning and synapse network formation during brain development to establish the cortical architecture. In this context, abnormal positioning of cortical neurons (a focal cortical dysplasia type 1a) has been observed in an autopsy sample from an epilepsy patient with a MUNC18–1 mutation (c.1631G > T; p.Gly544Val) [10]. These mutants are assumed to form aggregates with wild type MUNC-18-1, leading to proteasomal degradation, and lower the level of functional MUNC-18-1 [17, 18]
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