Abstract
The hippocampus is a brain area central for cognition. Mutations in the human SOX2 transcription factor cause neurodevelopmental defects, leading to intellectual disability and seizures, together with hippocampal dysplasia. We generated an allelic series of Sox2 conditional mutations in mouse, deleting Sox2 at different developmental stages. Late Sox2 deletion (from E11.5, via Nestin-Cre) affects only postnatal hippocampal development; earlier deletion (from E10.5, Emx1-Cre) significantly reduces the dentate gyrus (DG), and the earliest deletion (from E9.5, FoxG1-Cre) causes drastic abnormalities, with almost complete absence of the DG. We identify a set of functionally interconnected genes (Gli3, Wnt3a, Cxcr4, p73 and Tbr2), known to play essential roles in hippocampal embryogenesis, which are downregulated in early Sox2 mutants, and (Gli3 and Cxcr4) directly controlled by SOX2; their downregulation provides plausible molecular mechanisms contributing to the defect. Electrophysiological studies of the Emx1-Cre mouse model reveal altered excitatory transmission in CA1 and CA3 regions.
Highlights
The hippocampus is a brain region important for cognition, playing essential roles in learning and in spatial and episodic memory formation
neural stem cells (NSC) and intermediate neural progenitors (INP) will migrate from the dentate neural epithelium (DNE), along the dentate migratory stream (DMS), towards the forming hippocampal fissure (HF), a folding of the meninges that will be invaded by Cajal–Retzius cells (CRC)
We examined the expression of Cxcr4, a chemokine receptor expressed in INP and neuroblasts in the DMS and in CRC, and its ligand Cxcl12, expressed by the meninges, and required for the migration of INP and CRC [19,26,33,34]; we examined P73, a P53 homologue, marking CRC and important for hippocampal fissure and dentate gyrus (DG) formation [35,36]
Summary
The hippocampus is a brain region important for cognition, playing essential roles in learning and in spatial and episodic memory formation. Hippocampus defects (of genetic origin, or acquired) can lead to intellectual disability (ID), deficits of memory formation and epilepsy [1]. Understanding the developmental events and the genetic programme controlled by SOX2 during hippocampal embryogenesis, provides a key to understand how their perturbation can lead to hippocampal disease (in SOX2-mutant patients and, more in general, in hippocampal defects of genetic origin). The study of SOX2 binding to DNA in NSC proved instrumental in the identification of various Sox target genes, playing important roles in the development of different brain regions in vivo, such as the basal ganglia [9], the cerebellum [10] and the visual thalamus [11,12]
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