Expression of the RNA methyltransferase Nsun5 is essential for developing cerebral cortex

Abstract

Nsun5 gene, encoding a cytosine-5 RNA methyltransferase, is deleted in about 95% patients with Williams-Beuren syndrome (WBS). WBS is a neurodevelopmental disorder and characterized by cognitive disorder. We generated single-gene Nsun5 knockout ( Nsun5 -KO) mice and reported that the Nsun5 deletion leads to deficit in spatial cognition. This study focused on investigating the influence of Nsun5 deficiency in the development of cerebral cortex. In comparison with wild-type littermates, the cortical thickness in postnatal day 10 Nsun5 -KO mice was obviously reduced with an abnormal laminar organization, and the processes of pyramidal cells were shorter and finer. Nsun5 was selectively expressed in radial glial cells (RGCs) of cerebral cortex from embryonic day (E) 12.5 to E16.5, but not in intermediate progenitor cells (IPCs) or neocortical neurons. The Nsun5 deletion did not alter proliferation of RGCs or differentiation of RGCs into IPCs. Notably, the ablation of Nsun5 disrupted the growth of radial glial scaffolds, thus numerous basal processes of RGCs failed to reach pial basement membrane. Level of cell polarity regulator Cdc42 protein in radial glial scaffolds of E14.5 Nsun5 -KO mice was reduced, but the level of Cdc42 mRNA was unchanged. The dysfunction of glial scaffolds impeded the radial migration of upper-layer and deeper-layer neurons to cause their subcortical accumulation and apoptosis, resulting in an obvious thinness of the cortical plate in E18.5 Nsun5 -KO mice. These findings establish a critical role of Nsun5 in development of cerebral cortex through regulating radial glial scaffolds of RGCs to control migration of neocortical neurons. Electronic supplementary material The online version of this article (10.1186/s13041-019-0496-6) contains supplementary material, which is available to authorized users.

NSUN5 Facilitates Viral RNA Recognition by RIG-I Receptor

“…Ectopically expressed NSUN5 in the absence of RIG-I overexpression was mainly located in the nucleus (Supplemental Fig. 5A), which was consistent with previous reports (28,43). Interestingly, in our study, overexpression of RIG-I could induce the NSUN5 translocated from the nucleus to the cytoplasm.…”

“…NSUN5, an RNA methyltransferase, could modify the C3782 position of 28S rRNA. NSUN5 deficiency leads to an adaptive translational program for survival under cellular stress conditions in human glioma cells (28). Furthermore, NSUN5 has been implicated in regulating the lifespan of yeast and worms (29,30).…”

Dynamic transcriptomic m5C and its regulatory role in RNA processing

“…The unmethylated C3782 in 28S rRNA could restrain global protein synthesis, which promotes an adaptive translational program for stress survival in glioma (Janin et al, 2019). The absence of NSUN5 disrupts the glial scaffolds, leading to a restrained migration of upper and deeper‐layer neurons and consequently their subcortical accumulation and apoptosis as well as a distinct thinness of the cortical plate (Chen, Zhang, et al, 2019). NSUN5 is deleted in about 95% of patients with Williams–Beuren syndrome (WBS), one neurodevelopmental dysfunction, and cognitive abnormalities disease (Chen, Zhang, et al, 2019; Yuan, Chen, Zhang, Shen & Chen, 2019; Zhang et al, 2019).…”

Atypical Deletion of Williams-Beuren Syndrome Reveals the Mechanism of Neurodevelopmental Disorders

“…Moreover, several researchers have used atypical deletion patients and animal experiments to show that the genes located on the telomere side of WBSCR (i.e.,GTF2I, GTF2IRD1, and CLIP2) are the main causes of patients' behavior and cognitive phenotypes (6,7). Other scholars suggested that the deletion of WBSCR centromere-side genes also contributes to the speci c phenotype of WBS patients (8,9). This study describes nine cases of Chinese WBS patients with atypical deletions, one of which showed normal neurocognitive development.…”