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.
Highlights
Noonan syndrome (NS) is a congenital developmental disorder characterized by reduced growth, craniofacial abnormalities, heart defects and variable cognitive deficits [1]
Neurodevelopmental signals and neuronal activity are the main modulators of Ras/MAPK signaling, which regulates the expression of neuronal genes
We show that neurons expressing a RASopathy-related mutation fail to modulate their gene expression in response to neuronal activity
Summary
Noonan syndrome (NS) is a congenital developmental disorder characterized by reduced growth, craniofacial abnormalities, heart defects and variable cognitive deficits [1]. NS belongs to the RASopathies, a group of genetic diseases linked to mutations in genes coding for components or regulators of the Ras/mitogen-activated protein/extracellular signal-regulated kinase (Ras/MAPK) signaling cascade [2]. The dysregulation of this signaling pathway is believed to cause the pleiotropic phenotype associated with NS. NS-associated mutations in PTPN11 typically lead to an increased phosphatase activity of the enzyme [8,9,10], and in line with the positive regulatory role of Ptpn in Ras/ MAPK signaling, this pathway was shown to be hyperactive in NS [10]. Increased Ras/MAPK signaling seems to play a major role in the pathogenesis of NS-related defects, since several studies demonstrated that the inhibition of this signaling cascade by pharmacological inhibitors of the mitogen-activated protein kinase kinase (shortly called MEK) was able to fully or partially rescue cardiac [14,15] and craniofacial malformations [16], as well as defects in growth hormone release, which likely contribute to growth retardation seen in patients with NS [13]
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