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

Abstract

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.

Molecular mechanisms of corpus callosum development: a four-step journey

“…When Sema7a is inactivated, the neurons residing in the SVZ fail to polarize and neither develop an axon, nor leading process. Therefore, these neurons fail to migrate and extend an axon ( Bessa et al, 2023 ).…”