Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Language-Associated Gene SRPX2 Regulates Synapse Formation



Science 22 November 2013:  Vol. 342  no. 6161  pp. 987-991

The Human Language-Associated Gene SRPX2 Regulates Synapse Formation and Vocalization in Mice

G. M. Sia,  R. L. Clem,  R. L. Huganir

1Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

2Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

3Friedman Brain Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.


Synapse formation in the developing brain depends on the coordinated activity of synaptogenic proteins, some of which have been implicated in a number of neurodevelopmental disorders. Here, we show that the sushi repeat–containing protein X-linked 2 (SRPX2) gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the foxhead box protein P2 (FoxP2) transcription factor. We also show that FoxP2 modulates synapse formation through regulating SRPX2 levels and that SRPX2 reduction impairs development of ultrasonic vocalization in mice. Our results suggest FoxP2 modulates the development of neural circuits through regulating synaptogenesis and that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.

Synapse formation is an essential process during brain development that is coordinated by many membrane and secreted proteins. Proper development of neural circuitry is required for brain function, and mutations in synaptogenic genes have been linked to many cognitive diseases, including autism, schizophrenia, and mental retardation. Although a number of proteins have been shown to modulate synaptogenesis, no single gene knockout has been shown to completely ablate the formation of any major class of synapses, suggesting that the brain may use many proteins to regulate this process. To search for synaptogenic factors, we embarked on a high-throughput overexpression screen for human genes encoding membrane and secreted proteins that mediate synaptogenesis in the central nervous system. We identified sushi repeat–containing protein X-linked 2 (SRPX2) as a secreted protein that modulates synapse density in dissociated hippocampal neurons. The SRPX2 gene is mutated in human patients suffering from rolandic (sylvian) epilepsy with associated oral and speech dyspraxia and is a target of the FoxP2 gene, suggesting that SRPX2 may be involved in neural connectivity and language in humans. Although sushi domain proteins, also known as complement control protein (CCP) domain proteins, function as regulators of the immune system in vertebrates, they also regulate neuronal development in C. elegans and Drosophila. We therefore decided to further examine the role of SRPX2 in synapse formation.

To verify that SRPX2 controls synapse density, we overexpressed rat and human SRPX2 genes in dissociated rat cortical cells. Overexpression of SRPX2 caused an increase in the density of vesicular glutamate transporter 1 (VGlut1) and PSD-95 puncta on the neurons while leaving the density of inhibitory synaptic markers vesicular γ-aminobutyric acid (GABA) transporter (VGAT) and gephyrin unchanged. Dendritic morphology was unaffected by SRPX2 overexpression. Both human and rat SRPX2 genes are capable of increasing spine density when overexpressed. Thus, SRPX2 overexpression increases the density of excitatory synapses and spines in vitro without an effect on inhibitory synapse formation.

SRPX2 mRNA is found in neurons in multiple brain regions, including the cerebral cortex and hippocampus.

Because humans who bear mutated SRPX2 alleles suffer from electrical and morphological developmental defects in the language cortex that impair language acquisition, we wanted to examine whether SRPX2 knockdown can cause a similar defect in mice. When separated from their mothers, infant mouse pups emit ultrasonic vocalizations that elicit a search-and-retrieve behavior in nearby dams. The isolation-induced infant pup ultrasonic vocalization task has been widely used to characterize mouse models of human language, social, and arousal disorders, including mice containing FoxP2 mutations. We showed that dysregulation of SRPX2 results in impaired ultrasonic vocalization in infant mice.

We have shown that SRPX2 is a sushi domain protein involved in synapse formation. In invertebrates, sushi domain proteins have been shown to cluster AChRs at synapses in C. elegans and is localized to the nascent synaptic cleft in Drosophila. In vertebrates, sushi domain proteins are primarily studied as regulators of the classical complement cascade. Our results suggest that sushi domain proteins may also play roles in regulating synaptic development and organization in vertebrates. In addition, because genes of the classical complement cascade have been shown to regulate synapse elimination, we speculate that SRPX2 may act through modulation of components of the complement cascade.

To date, FoxP2 is the only gene that has been shown to be involved in a human monogenic language disorder, although the cellular mechanisms involved remain obscure. Previous studies have suggested that FoxP2 may regulate neurite growth, dendritic morphology, and synaptic physiology of basal ganglia neurons. We show here that FoxP2 can regulate synaptogenesis of excitatory synapses in cortical neurons through SRXP2. We show here that FoxP2 is an activity-independent transcription factor that regulates synaptogenesis through SRPX2. Our study suggests that FoxP2 can affect the development of language-related neural circuitry through regulating synaptogenesis, and that SRPX2 may be involved in the pathogenesis of language disorders.

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