title: Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.
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.
authors.affiliation: Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Kwan
authors.forename: Mandy M S
authors.initials: MM
authors.lastname: Lam
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Johnson
authors.forename: Umber
authors.initials: U
authors.lastname: Dube
authors.forename: Sungbo
authors.initials: S
authors.lastname: Shim
authors.forename: Mladen-Roko
authors.initials: MR
authors.lastname: Rašin
authors.forename: André M M
authors.initials: AM
authors.lastname: Sousa
authors.forename: Sofia
authors.initials: S
authors.lastname: Fertuzinhos
authors.forename: Jie-Guang
authors.initials: JG
authors.lastname: Chen
authors.forename: Jon I
authors.initials: JI
authors.lastname: Arellano
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Chan
authors.forename: Mihovil
authors.initials: M
authors.lastname: Pletikos
authors.forename: Lana
authors.initials: L
authors.lastname: Vasung
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schwartz
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Pasko
authors.initials: P
authors.lastname: Rakic
authors.forename: Marija
authors.initials: M
authors.lastname: Heffer
authors.forename: Ivica
authors.initials: I
authors.lastname: Kostović
authors.forename: Milos
authors.initials: M
authors.lastname: Judaš
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000196:embryology* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D013045:Species Specificity
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D052248:Nitric Oxide Synthase Type I; C497684:Fmr1 protein, mouse