Cell Reports (Dec 2016)
A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior
- Ingrid Ehrmann,
- Matthew R. Gazzara,
- Vittoria Pagliarini,
- Caroline Dalgliesh,
- Mahsa Kheirollahi-Chadegani,
- Yaobo Xu,
- Eleonora Cesari,
- Marina Danilenko,
- Marie Maclennan,
- Kate Lowdon,
- Tanja Vogel,
- Piia Keskivali-Bond,
- Sara Wells,
- Heather Cater,
- Philippe Fort,
- Mauro Santibanez-Koref,
- Silvia Middei,
- Claudio Sette,
- Gavin J. Clowry,
- Yoseph Barash,
- Mark O. Cunningham,
- David J. Elliott
Affiliations
- Ingrid Ehrmann
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Matthew R. Gazzara
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Vittoria Pagliarini
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome and Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy
- Caroline Dalgliesh
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Mahsa Kheirollahi-Chadegani
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Yaobo Xu
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Eleonora Cesari
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome and Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy
- Marina Danilenko
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Marie Maclennan
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Kate Lowdon
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Tanja Vogel
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Medical Faculty, University of Freiburg, 79104 Freiburg, Germany
- Piia Keskivali-Bond
- Mary Lyon Centre, MRC Harwell Institute, Oxfordshire OX11 ORD, UK
- Sara Wells
- Mary Lyon Centre, MRC Harwell Institute, Oxfordshire OX11 ORD, UK
- Heather Cater
- Mary Lyon Centre, MRC Harwell Institute, Oxfordshire OX11 ORD, UK
- Philippe Fort
- Université Montpellier, UMR 5237, Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier 34293, France
- Mauro Santibanez-Koref
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Silvia Middei
- Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche, Via E. Ramarini 32, 00015 Monterotondo Scalo-Roma, Italy
- Claudio Sette
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome and Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy
- Gavin J. Clowry
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- Yoseph Barash
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Mark O. Cunningham
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- David J. Elliott
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- DOI
- https://doi.org/10.1016/j.celrep.2016.12.002
- Journal volume & issue
-
Vol. 17,
no. 12
pp. 3269 – 3280
Abstract
The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.
Keywords
- RNA-seq
- alternative splicing
- gene expression
- transcriptome
- Neurexin splicing
- RNA binding proteins
- neuron
- hippocampus
- brain
