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.
Highlights
Williams-Beuren syndrome (WBS) is a contiguous gene deletion disorder [1] that is caused by spontaneous deletions of 1.5 million to 1.8 million base pairs comprising 26 to 28 genes on human chromosome 7q11.23 [2]
Selective expression of Nsun5 in Radial glial cell (RGC) of developing cerebral cortex To explore the mechanisms underlying Nsun5 deletionimpaired development of cerebral cortex, we primarily examined the expression of Nsun5 in cerebral cortex of WT mice from E10.5 to PND10 by RT-PCR and Western blotting (n = 6 mice per experimental group)
The Nsun5 protein was selectively expressed in radial glial cells during embryonic cortex
Summary
Williams-Beuren syndrome (WBS) is a contiguous gene deletion disorder [1] that is caused by spontaneous deletions of 1.5 million to 1.8 million base pairs comprising 26 to 28 genes on human chromosome 7q11.23 [2]. Using probes containing parts of the elastin gene, the deletion has readily been detected in approximately 90–99% WBS patients [3]. WBS is characterized by an unusual cognitive profile that includes relatively preserved expressive language, facial processing abilities and dramatic deficits in spatial cognition [4,5,6]. The Nsun gene, which encodes a cytosine-5 RNA methyltransferase, is included in the WBS deletion [2, 12]. The deletion of Nsun has been reported in about 95% patients with WBS [2]. Zhang et al have recently reported that single-gene Nsun knockout homozygous (Nsun5KO) mice show the phenotype of spatial cognitive defects [13]. The whole brain volume in patients with WBS has been reported to be reduced by 13% [14].
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