Abstract
Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Genetic deletion of the Agrn gene in excitatory neurons decreases NSPCs proliferation and increases depressive-like behavior. Low-density lipoprotein receptor-related protein 4 (Lrp4), a receptor for Agrin, is expressed in hippocampal NSPCs and its mutation blocked basal as well as EE-induced NSPCs proliferation and maturation of newborn neurons. Finally, we show that Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2); and Ror2 mutation impairs NSPCs proliferation. Together, these observations identify a role of Agrin-Lrp4-Ror2 signaling for adult neurogenesis, uncovering previously unexpected functions of Agrin and Lrp4 in the brain.
Highlights
Brains change their structure and function in response to environmental alterations
Compared with mice that were housed in standard cages (SC), mice housed in EE cages displayed more Arc+ granule cells in the dental gyrus region of the hippocampus (Figure 1B and C), in agreement with previous reports (Pinaud et al, 2001)
Adult hippocampal neurogenesis may be a mechanism for the brain to adapt to environmental changes
Summary
Brains change their structure and function in response to environmental alterations. One such adaptation mechanism is to form new neurons and circuits. NSPCs line in the sub-granule zone (SGZ) and proliferate to generate newborn neurons that integrate into the granule cell layer of the dentate gyrus (DG) (Goncalves et al, 2016). This dynamic process includes quiescent stem cell activation, proliferation, neuronal fate specification, migration and synaptic integration (Ming and Song, 2011). Ensuing signaling leads to multiple events including concentration of acetylcholine receptors and presynaptic differentiation and eventual formation of the peripheral synapse (Li et al, 2018) Both Agrin and Lrp are expressed in the brain (Gesemann et al, 1998; Sun et al, 2016). Our results suggest a working model where Agrin via Lrp activates the receptor tyrosine kinase Ror to promote adult neurogenesis
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