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

KY Kwan, MMS Lam, MB Johnson, U Dube, S Shim, MR Rasin, AMM Sousa, S Fertuzinhos, JG Chen, JI Arellano, DW Chan, M Pletikos, L Vasung, DH Rowitch, EJ Huang, ML Schwartz, Rob Willemsen, Ben Oostra, P Rakic, M HefferI Kostovic, M Judas, N Sestan

Research output: Contribution to journalArticleAcademicpeer-review

107 Citations (Scopus)


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.
Original languageUndefined/Unknown
Pages (from-to)899-911
Number of pages13
Issue number4
Publication statusPublished - 2012

Research programs

  • EMC MGC-02-96-01

Cite this