Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior

Dong Sun,Jin-Xiu Pan,Xiang-Dong Sun,Fu-Lei Tang,Lu Zhao,Lin Mei,Jin-Xia Hu,Wen-Cheng Xiong,Dae-Hoon Lee,Xiao-Juan Zhu

doi:10.1038/s41419-017-0019-2

Dong Sun, Jin-Xiu Pan + Show 8 more

Open Access

https://doi.org/10.1038/s41419-017-0019-2

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Abstract

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

Highlights

In adult mammalian brains, two neurogenic regions retain the ability to generate new neurons[1]
We are all aware that the subgranule zone (SGZ) is enriched in exuberant neuronal communications between mature granule neurons and inhibitory interneurons[16], major neurotransmitters like Glutamate and GABA have long been implicated in regulating adult hippocampal neurogenesis[17,18]
Neogenin expression in neural stem cells (NSCs)/neural progenitor cells (NPCs) and immature neurons in adult mouse hippocampal dentate gyrus (DG) To investigate neogenin’s function in adult hippocampus, we first examined its expression by taking advantage of LacZ reporter in neogenin mutant mice

Summary

Introduction

Two neurogenic regions retain the ability to generate new neurons[1]. It is the subventricular zone (SVZ) of the lateral ventricular region, which generates neuroblasts that migrate into olfactory bulb (OB) through the rostral migratory stream and differentiate into GABA and dopamineproducing interneurons[2,3]. It is the subgranular zone of dental gyrus (DG) of hippocampus, which gives. Mature granule neurons were thought to compete with new-born neurons for synaptic inputs, and further affected NSCs activation[19]

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