TY - JOUR
T1 - Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex
AU - Kwan, KY
AU - Lam, MMS
AU - Johnson, MB
AU - Dube, U
AU - Shim, S
AU - Rasin, MR
AU - Sousa, AMM
AU - Fertuzinhos, S
AU - Chen, JG
AU - Arellano, JI
AU - Chan, DW
AU - Pletikos, M
AU - Vasung, L
AU - Rowitch, DH
AU - Huang, EJ
AU - Schwartz, ML
AU - Willemsen, Rob
AU - Oostra, Ben
AU - Rakic, P
AU - Heffer, M
AU - Kostovic, I
AU - Judas, M
AU - Sestan, N
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2012.02.060
DO - 10.1016/j.cell.2012.02.060
M3 - Article
C2 - 22579290
SN - 0092-8674
VL - 149
SP - 899
EP - 911
JO - Cell
JF - Cell
IS - 4
ER -