1. Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex
- Author
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Miloš Judaš, Ben A. Oostra, David H. Rowitch, Mihovil Pletikos, Jie Guang Chen, Kenneth Y. Kwan, Pasko Rakic, Rob Willemsen, Marija Heffer, Lana Vasung, Daniel W. Chan, Eric J. Huang, Nenad Sestan, Ivica Kostović, Mandy M. Lam, Michael L. Schwartz, Sungbo Shim, André M. M. Sousa, Jon I. Arellano, Mladen-Roko Rasin, Sofia Fertuzinhos, Matthew B. Johnson, Umber Dube, and Clinical Genetics
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Neurogenesis ,NOS1 ,Synaptogenesis ,Nitric Oxide Synthase Type I ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Fragile X Mental Retardation Protein ,Mice ,Species Specificity ,cerebral cortex ,development ,FMRP ,medicine ,Animals ,Humans ,RNA Processing, Post-Transcriptional ,Cerebral Cortex ,Mice, Knockout ,Regulation of gene expression ,Neocortex ,Biochemistry, Genetics and Molecular Biology(all) ,Pyramidal Cells ,Translation (biology) ,Anatomy ,medicine.disease ,nervous system diseases ,Fragile X syndrome ,medicine.anatomical_structure ,Gene Expression Regulation ,Cerebral cortex ,Fragile X Syndrome ,Neuroscience - Abstract
Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here we show that FMRP regulates the translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is ubiquitously expressed, NOS1 protein is transiently co-expressed with FMRP during early synaptogenesis in layer- and region-specific subpopulations of pyramidal neurons. These include mid-fetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca’s area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases but not FMRP-deficient mice. Thus, alterations in FMRP post-transcriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.
- Published
- 2012