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Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.
Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.
- Source :
-
Cell [Cell] 2012 May 11; Vol. 149 (4), pp. 899-911. - Publication Year :
- 2012
-
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 translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer- and region-specific pyramidal neurons. These include midfetal 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 posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cerebral Cortex metabolism
Fragile X Mental Retardation Protein genetics
Fragile X Syndrome metabolism
Fragile X Syndrome physiopathology
Gene Expression Regulation
Humans
Mice
Mice, Knockout
Neurogenesis
Pyramidal Cells metabolism
RNA Processing, Post-Transcriptional
Species Specificity
Cerebral Cortex embryology
Fragile X Mental Retardation Protein metabolism
Fragile X Syndrome embryology
Nitric Oxide Synthase Type I metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 149
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 22579290
- Full Text :
- https://doi.org/10.1016/j.cell.2012.02.060