Cell
Volume 149, Issue 4, 11 May 2012, Pages 899-911
Journal home page for Cell

Article
Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex

https://doi.org/10.1016/j.cell.2012.02.060Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► NOS1 and FMRP are coexpressed in subsets of pyramidal neurons in human fetal brain ► FMRP directly interacts with motifs present in human, but not mouse, NOS1 mRNA ► NOS1 translation is increased by FMRP in a species-dependent manner ► NOS1 protein levels are severely reduced in developing human fragile X neocortex

Cited by (0)