Sema7A and Sema4D Heterodimerization is Essential for Membrane Targeting and Neocortical Wiring

Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving intellectual disability, speech delay, epilepsy and craniofacial defects. We show that Satb2 controls neuronal migration and axonal outgrowth by inducing the expression of the GPI-anchored protein, Sema7A. We find that heterodimerization with Sema4D increases targeting of Sema4D to the membrane and is required for Sema7A function. Finally, we report that membrane localization and pos- translational modification of the Sema7A-Sema4D complex is disrupted by a novel de novo mutation in Sema4D (Q497P) that is associated with epilepsy in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/527998v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@db698org.highwire.dtl.DTLVardef@4ee980org.highwire.dtl.DTLVardef@c3d9d6org.highwire.dtl.DTLVardef@12a135_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISema7A is a direct Satb2 target that drives neuronal migration and axon outgrowth C_LIO_LISema7A exerts its effect by heterodimerizing with Sema4D at neurites and growth cones C_LIO_LISema7A increases cell surface localization of Sema4D C_LIO_LIDe novo human Sema4D-Q497P mutation causes epilepsy, inhibits post-translational processing & surface localization C_LI eTOCSema7A is a direct target of the transcription factor Satb2. Sema7A promotes normal migration and axon outgrowth in cortical neurons by modulating reverse signaling via Sema4D. These processes are dependent on Sema7A-Sema4D heterodimerization and membrane localization; insufficient transcription of Sema7A or incomplete glycosylation of Sema4D inhibit this progression.