Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis

Abstract

SUMMARY Adult neurogenesis, a process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying activity-dependent regulation of sequential steps of adult neurogenesis remains largely unknown. Here we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth and spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests a novel activity-dependent mechanism governing adult neurogenesis via acute release of tonic inhibition.

Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain

“…Given that adult neural stem cells are dynamically regulated by their local environment, including neuronal activity modulation (34,35), our findings have significant implications for understanding how individual neural stem cells could impact the function of the existing microcircuitry via delivery of newborn neurons that are primed to undergo a critical period of enhanced plasticity (36). Our findings also provide a framework in which to investigate the aberrant migration of newborn granule cells under pathological conditions, such as epilepsy (37,38).…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Loss of Dickkopf-1 (Dkk-1), which normally inhibits Wnt/β-catenin signaling by binding to LRP5/6, increases the number of neural progenitors in the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 hippocampus [129]. In addition, lentivirus-mediated knockdown of the Wnt antagonist secreted frizzled related protein 3 (sFRP3 or FRZB) in the dentate gyrus increases canonical Wnt signaling, neural progenitor proliferation and neuronal development [130]. These observations suggest that secreted Wnt antagonists promote functional homeostasis in the niche during adult neurogenesis.…”

Heat-Induced Antigen Retrieval: An Effective Method to Detect and Identify Progenitor Cell Types during Adult Hippocampal Neurogenesis

“…Our approach is simple to use requiring mostly already available tools and reagents in the laboratory. We have utilized it extensively to study development of neural stem cells and their regulation via intrinsic genetic or extrinsic environmental factors 8 .…”