title: Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy.
abstract: Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity-induced signaling and regulation of gene expression in Ptpn11D61Y mice and suggests that these deficits contribute to the pathophysiology of cognitive impairments in NS.
authors.affiliation: RG Presynaptic Plasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.|Institute for Human Genetics, Otto von Guericke-University, Magdeburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Altmüller
authors.affiliation: RG Presynaptic Plasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Santosh
authors.identifier: 0000-0002-1417-754X
authors.initials: S
authors.lastname: Pothula
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Anil
authors.identifier: 0000-0002-6743-8627
authors.initials: A
authors.lastname: Annamneedi
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Saeideh
authors.initials: S
authors.lastname: Nakhaei-Rad
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Montenegro-Venegas
authors.affiliation: RG Presynaptic Plasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Eneko
authors.initials: E
authors.lastname: Pina-Fernández
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marini
authors.affiliation: Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Santos
authors.affiliation: Institute for Human Genetics, Otto von Guericke-University, Magdeburg, Germany.
authors.forename: Denny
authors.identifier: 0000-0003-2748-9929
authors.initials: D
authors.lastname: Schanze
authors.affiliation: Neurogenetics Special Laboratory, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Dirk
authors.identifier: 0000-0002-4964-1330
authors.initials: D
authors.lastname: Montag
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ahmadian
authors.affiliation: Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany.|Center for Behavioral Brain Science, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stork
authors.affiliation: Institute for Human Genetics, Otto von Guericke-University, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: RG Presynaptic Plasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.|Center for Behavioral Brain Science, Otto von Guericke University, Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Anna
authors.identifier: 0000-0002-1815-4409
authors.initials: A
authors.lastname: Fejtova
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D018631:ras Proteins