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

Abstract

Synapse formation in the developing brain depends on the coordinated activity of synaptogenic proteins, some which have been implicated in a number of neurodevelopmental disorders. Here, we show that the sushi repeat-containing domain 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.

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

“…Since the Foxp1 +/− mice used in this study were whole-body knockouts and because Foxp1 has been shown to regulate the development of a host of organ systems (Wang et al 2004;Hu et al 2006;Shu et al 2007;Dasen et al 2008;Rousso et al 2008), it cannot be entirely ruled out that the behavioral phenotypes displayed by these mice are secondary to the peripheral consequences of the knockout. Additionally, it should be noted that other brain regions besides the striatum, such as the neocortex, are known to both express Foxp1 and contribute to the production of USVs (Hisaoka et al 2010;Sia et al 2013). Moreover, while this study focused on a patient-relevant model of FOXP1 function (namely, haploinsufficiency), at least one study has demonstrated increased FOXP1 expression in lymphoblastoid cell lines from ASD patients (Chien et al 2013).…”

What can mice tell us about Foxp2 function?

“…One such target is SRPX2, mutations of which lead to epilepsy in speech-related areas of the brain and DVD/CAS [38 ]. Recently, SRPX2 knockdown was shown to impair synaptogenesis and lead to reduced ultrasonic vocalisation of P7 mouse pups (see below for discussion of rodent vocalisations) [39 ]. Together these data hint at common molecular and circuit mechanisms that cross diagnostic borders.…”

A Molecular Genetic Perspective on Speech and Language

“…(However, see Lesca et al (2013) for evidence that casts doubt on the role of uPAR/ SRPX2 in this disorder, instead implicating a different gene, GRIN2A). Intriguingly, SRPX2 regulation by FOXP2 is thought to be an important mediator of synaptogenesis (Sia, Clem, & Huganir, 2013). Other FOXP2 targets of particular clinical relevance include the receptor tyrosine kinase MET, proposed as a candidate for autism (Mukamel et al, 2011), and DISC1, a gene that was originally implicated in schizophrenia (Walker et al, 2012).…”