Mutations in NONO Lead to Syndromic Intellectual Disability and Inhibitory Synaptic Defects

Overview

Journal Nat Neurosci

Date 2015 Nov 17

PMID 26571461

Citations 44

Authors

Dennis Mircsof

Maeva Langouet

Marlene Rio

Sebastien Moutton

Karine Siquier-Pernet

Christine Bole-Feysot

Nicolas Cagnard

Patrick Nitschke

Ludmila Gaspar

Matej Znidaric

Olivier Alibeu

Ann-Kristina Fritz

David P Wolfer

Aileen Schroter

Giovanna Bosshard

Markus Rudin

Christina Koester

Florence Crestani

Petra Seebeck

Nathalie Boddaert

Katrina Prescott

Rochelle Hines

Steven J Moss

Jean-Marc Fritschy

Arnold Munnich

Jeanne Amiel

Steven A Brown

Shiva K Tyagarajan

Laurence Colleaux

Affiliations

Soon will be listed here.

Abstract

The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.

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References

Mohajeri M, Saini K, Li H, Crameri A, Lipp H, Wolfer D . Intact spatial memory in mice with seizure-induced partial loss of hippocampal pyramidal neurons. Neurobiol Dis. 2003; 12(3):174-81. DOI: 10.1016/s0969-9961(02)00031-1. View

Notter T, Panzanelli P, Pfister S, Mircsof D, Fritschy J . A protocol for concurrent high-quality immunohistochemical and biochemical analyses in adult mouse central nervous system. Eur J Neurosci. 2013; 39(2):165-75. DOI: 10.1111/ejn.12447. View

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

Kowalska E, Ripperger J, Hoegger D, Bruegger P, Buch T, Birchler T . NONO couples the circadian clock to the cell cycle. Proc Natl Acad Sci U S A. 2012; 110(5):1592-9. PMC: 3562797. DOI: 10.1073/pnas.1213317110. View

Tyagarajan S, Fritschy J . Gephyrin: a master regulator of neuronal function?. Nat Rev Neurosci. 2014; 15(3):141-56. DOI: 10.1038/nrn3670. View

Jacob T, Bogdanov Y, Magnus C, Saliba R, Kittler J, Haydon P . Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors. J Neurosci. 2005; 25(45):10469-78. PMC: 6725824. DOI: 10.1523/JNEUROSCI.2267-05.2005. View

Zhang G, Neubert T, Jordan B . RNA binding proteins accumulate at the postsynaptic density with synaptic activity. J Neurosci. 2012; 32(2):599-609. PMC: 3561928. DOI: 10.1523/JNEUROSCI.2463-11.2012. View

Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T . Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012; 380(9854):1674-82. DOI: 10.1016/S0140-6736(12)61480-9. View

Lardi-Studler B, Smolinsky B, Petitjean C, Koenig F, Sidler C, Meier J . Vertebrate-specific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering. J Cell Sci. 2007; 120(Pt 8):1371-82. DOI: 10.1242/jcs.003905. View

10.

Mullen S, Carvill G, Bellows S, Bayly M, Trucks H, Lal D . Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 2013; 81(17):1507-14. PMC: 3888172. DOI: 10.1212/WNL.0b013e3182a95829. View

11.

Lehner M, Wislowska-Stanek A, Skorzewska A, Maciejak P, Szyndler J, Turzynska D . Differences in the density of GABA-A receptor alpha-2 subunits and gephyrin in brain structures of rats selected for low and high anxiety in basal and fear-stimulated conditions, in a model of contextual fear conditioning. Neurobiol Learn Mem. 2010; 94(4):499-508. DOI: 10.1016/j.nlm.2010.09.001. View

12.

Kuwahara S, Ikei A, Taguchi Y, Tabuchi Y, Fujimoto N, Obinata M . PSPC1, NONO, and SFPQ are expressed in mouse Sertoli cells and may function as coregulators of androgen receptor-mediated transcription. Biol Reprod. 2006; 75(3):352-9. DOI: 10.1095/biolreprod.106.051136. View

13.

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

14.

Dong X, Sweet J, Challis J, Brown T, Lye S . Transcriptional activity of androgen receptor is modulated by two RNA splicing factors, PSF and p54nrb. Mol Cell Biol. 2007; 27(13):4863-75. PMC: 1951499. DOI: 10.1128/MCB.02144-06. View

15.

Dunkley P, Jarvie P, Robinson P . A rapid Percoll gradient procedure for preparation of synaptosomes. Nat Protoc. 2008; 3(11):1718-28. DOI: 10.1038/nprot.2008.171. View

16.

Fritschy J, Mohler H . GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol. 1995; 359(1):154-94. DOI: 10.1002/cne.903590111. View

17.

Gallagher M, Burwell R, Burchinal M . Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behav Neurosci. 1993; 107(4):618-26. DOI: 10.1037//0735-7044.107.4.618. View

18.

Brunig I, Suter A, Knuesel I, Luscher B, Fritschy J . GABAergic terminals are required for postsynaptic clustering of dystrophin but not of GABA(A) receptors and gephyrin. J Neurosci. 2002; 22(12):4805-13. PMC: 6757720. View

19.

Fox A, Bond C, Lamond A . P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner. Mol Biol Cell. 2005; 16(11):5304-15. PMC: 1266428. DOI: 10.1091/mbc.e05-06-0587. View

20.

Kowalska E, Ripperger J, Muheim C, Maier B, Kurihara Y, Fox A . Distinct roles of DBHS family members in the circadian transcriptional feedback loop. Mol Cell Biol. 2012; 32(22):4585-94. PMC: 3486183. DOI: 10.1128/MCB.00334-12. View