MUNC18–1 gene abnormalities are involved in neurodevelopmental disorders through defective cortical architecture during brain development

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0498-5) contains supplementary material, which is available to authorized users.

De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A

“…We propose that a comparative analysis based on MD simulations for calculating the deviation in protein-protein interaction energy, be applied to other complexes for which high-resolution X-ray structures are available. (Hamada, Iwamoto, Tabata, & Nagata, 2017). However, in the patient reported in this study, no brain developmental or structural alterations were observed, thus F I G U R E 5 Model for STXBP1 pathology and clinical manifestation of R39dup mutant protein.…”

Biochemical and Morphological Characterization of a Guanine Nucleotide Exchange Factor ARHGEF9 in Mouse Tissues

“…Then, gentle dissociation of neuronal cells was performed with trypsin (0.25%) and mechanical disruption was done to separate cells from connective tissue while providing minimum damage to individual neuronal cells [ 19 ]. The isolated neurons were cultured essentially as described [ 3 , 6 ]. Transient transfection was carried out using Lipofectamine 2000 (Life Technologies).…”

The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders

“…Examples of mucus release components that overlap with synaptic neurotransmitter systems include syntaxin, Munc 18, VAMP, and SNAP proteins. These vesicleassociated proteins are commonly expressed at neuronal synaptic membranes and have been identified as being mutated in neurological disorders (syntaxin; ASD, SNAP; ADHD, Munc 18; epilepsy/ASD (Guerini et al, 2011;Durdiaková et al, 2014;Hamada et al, 2017). Changes in the function of these proteins will not only contribute to brain disorders but may also disrupt vesicular secretion of mucus.…”