Transcription Factor 4 Safeguards Hippocampal Dentate Gyrus Development by Regulating Neural Progenitor Migration

Abstract

The dentate gyrus (DG) of the hippocampal formation plays essential roles in learning and memory. Defective DG development is associated with neurological disorders. Here, we show that transcription factor 4 (Tcf4) is essential for DG development. Tcf4 expression is elevated in neural progenitors of the dentate neuroepithelium in the developing mouse brain. We demonstrate that conditional disruption of Tcf4 in the dentate neuroepithelium leads to abnormal neural progenitor migration guided by disorganized radial glial fibers, which further leads to hypoplasia in the DG. Moreover, we reveal that Wnt7b is a key downstream effector of Tcf4 in regulating neural progenitor migration. Behavioral analysis shows that disruption of integrity of the DG impairs the social memory highlighting the importance of proper development of the DG. These results reveal a critical role for Tcf4 in regulating DG development. As mutations in TCF4 cause Pitt–Hopkins syndrome (PTHS) characterized by severe intellectual disability, our data also potentially provide insights into the basis of neurological defects linked to TCF4 mutations.

Enriched Environment Ameliorates Adult Hippocampal Neurogenesis Deficits in Tcf4 Haploinsufficient Mice

“…TCF4 is highly expressed in the dentate neuroepithelium and the developing hippocampus (12,13). Considering recent ndings that TCF4 dosage affects proliferation of embryonic neural precursor cells (14-16) and cell migration in the developing CNS (14, 17) including the migration of hippocampal neural progenitors (12), it is tempting to speculate that a combination of proliferation and migration defects of neural precursors contribute to the decreased size of the neural stem/progenitor cell pool in the adult dentate gyrus. TCF4 and the related E-protein TCF3 inhibit neural stem cell differentiation and cell cycle exit in the adult subventricular zone (37) raising the alternative possibility that Tcf4 haploinsu ciency results in accelerated stem cell depletion due to premature differentiation.…”

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

“…Radial-glia like stem / progenitor cells in the murine dentate gyrus are derived from neural precursor cells in the mouse dentate neuroepithelium, which migrate into the primitive dentate region and enter quiescence around postnatal day 7. TCF4 is highly expressed in the dentate neuroepithelium and the developing hippocampus (12,13). Considering recent ndings that TCF4 dosage affects proliferation of embryonic neural precursor cells (14-16) and cell migration in the developing CNS (14, 17) including the migration of hippocampal neural progenitors (12), it is tempting to speculate that a combination of proliferation and migration defects of neural precursors contribute to the decreased size of the neural stem/progenitor cell pool in the adult dentate gyrus.…”

“…TCF4 is highly expressed in the dentate neuroepithelium and the developing hippocampus (12,13). Considering recent ndings that TCF4 dosage affects proliferation of embryonic neural precursor cells (14-16) and cell migration in the developing CNS (14, 17) including the migration of hippocampal neural progenitors (12), it is tempting to speculate that a combination of proliferation and migration defects of neural precursors contribute to the decreased size of the neural stem/progenitor cell pool in the adult dentate gyrus. TCF4 and the related E-protein TCF3 inhibit neural stem cell differentiation and cell cycle exit in the adult subventricular zone (37) raising the alternative possibility that Tcf4 haploinsu ciency results in accelerated stem cell depletion due to premature neuronal fate commitment.…”

“…TCF4 is broadly expressed throughout the developing human and murine cortex and hippocampus (12)(13)(14). TCF4 has pleiotropic functions in neurodevelopment.…”

“…MR-analyses uncovered small hippocampi in individuals with PTHS (13,20). Heterozygote Tcf4 knockout mice show a signi cant reduction in hippocampal volume (13), while homozygote TCF4 knockout mice and transgenic mice with a homozygote embryonic neural stem cell speci c-deletion of TCF4 show severe hippocampal hypoplasia (12,17,19). TCF4 is also highly expressed in the adult brain (13), and is thought to have critical function in the regulation of neural plasticity (21)(22)(23).…”