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

Science  22 Nov 2013:
Vol. 342, Issue 6161, pp. 987-991
DOI: 10.1126/science.1245079

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The transcription factor FoxP2 (forkhead box P2) affects language acquisition in humans and regulates the protein SRPX2 (sushi repeat-containing protein X-linked 2), which itself also affects language. Sia et al. (p. 987, published online 31 October; see the Perspective by Lieberman) found that in the mouse brain, the FoxP2 transcription factor binds to the SRPX2 gene. In tissue culture experiments, FoxP2, but not SRPX2, affected dendritic morphology, while both FoxP2 and SRPX2 affected the formation of excitatory synapses. Overexpression of SRPX2 in the mouse brain equivalent of the human brain's language area affected synapse density and disrupted the ultrasonic vocalizations emitted by mouse pups in search of their mothers.

Abstract

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.

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