Genetic studies point to a major role of de novo mutations in neurodevelopmental disorders of intellectual disability, autism spectrum disorders, and epileptic encephalopathy. The STXBP1 gene encodes the syntaxin-binding protein 1 (Munc18–1) that critically controls synaptic vesicle exocytosis and synaptic transmission. This gene harbors a high frequency of de novo mutations, which may play roles in these neurodevelopmental disorders. However, the system and behavioral-level pathophysiological changes caused by these genetic defects remain poorly understood. Constitutional (Stxbp1+/−), dorsal-telencephalic excitatory (Stxbp1fl/+/Emx), or global inhibitory neuron-specific (Stxbp1fl/+/Vgat) mice were subjected to a behavioral test battery examining locomotor activity, anxiety, fear learning, and social interactions including aggression. Furthermore, measurements of local field potentials in multiple regions of the brain were performed. Stxbp1+/− male mice exhibited enhanced aggressiveness and impaired fear learning associated with elevated gamma activity in several regions of the brain including the prefrontal cortex. Stxbp1fl/+/Emx mice showed fear-learning deficits, but neither Stxbp1fl/+/Emx nor Stxbp1fl/+/Vgat mice showed increased aggressiveness. Pharmacological potentiation of the excitatory transmission at active synapses via the systemic administration of ampakine CX516, which enhances the excitatory postsynaptic function, ameliorated the aggressive phenotype of Stxbp1+/− mice. These findings suggest that synaptic impairments of the dorsal telencephalic and subcortical excitatory neurons cause learning deficits and enhanced aggression in Stxbp1+/− mice, respectively. Additionally, normalizing the excitatory synaptic transmission is a potential therapeutic option for managing aggressiveness in patients with STXBP1 mutations.
Mouse lefty1 and lefty2 genes are expressed on the left side of developing embryos and are required for left-right determination. Here we have studied expression and transcriptional regulatory mechanisms of human LEFTY genes.The human LEFTY locus comprises two functional genes (LEFTY1 and LEFTY2) and a putative pseudogene. LEFTY1 is expressed in colon crypts. However, whereas LEFTY1 mRNA is present in basal cells of the crypts, LEFTY1 protein is localized in the apical region, suggesting that this secreted protein undergoes long-range transport. Human LEFTY2 possesses a left side-specific enhancer (ASE) like mouse lefty2; however, the LEFTY2 ASE shows markedly higher activity in the floor plate than does the lefty2 ASE. In contrast to mouse lefty1, which is expressed predominantly in the floor plate under the control of a right side-specific silencer, human LEFTY1 is expressed mainly in left lateral plate mesoderm under the control of an ASE-like left side-specific enhancer. The presence of FAST-binding sites in the LEFTY1 enhancer (and their absence in lefty1) contributes to the difference.These observations suggest that humans and mice have acquired distinct strategies during evolution for determining the asymmetric expression of LEFTY and lefty genes.
A 50-year-old woman was referred to our hospital for consultation for a suspected left adrenal tumor detected by ultrasonography during a health check. Computed tomography and magnetic resonance imaging revealed a 4.7×3.4 cm tumor in the retroperitoneal space near the adrenal gland. The patient subsequently underwent laparoscopic tumor resection. Using fluorescence in situ hybridization (FISH), the resected tumor was diagnosed as a retroperitoneal bronchial cyst. Here we present a case of a definitive diagnosis of a retroperitoneal bronchial cyst using FISH, and review the cases of retroperitoneal bronchial cyst in the literature.
