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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.

Authors :
Kwan KY
Lam MM
Johnson MB
Dube U
Shim S
Rašin MR
Sousa AM
Fertuzinhos S
Chen JG
Arellano JI
Chan DW
Pletikos M
Vasung L
Rowitch DH
Huang EJ
Schwartz ML
Willemsen R
Oostra BA
Rakic P
Heffer M
Kostović I
Judaš M
Sestan N
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.)

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