Abstract
Class 3 semaphorins are well-known axonal guidance cues during the embryonic development of mammalian nervous system. However, their activity on postnatally differentiated neurons in neurogenic regions of adult brains has not been characterized. We found that silencing of semaphorin receptors neuropilins (NRP) 1 or 2 in neural progenitors at the adult mouse dentate gyrus resulted in newly differentiated neurons with shorter dendrites and simpler branching in vivo. Tyrosine phosphorylation (Tyr 397) and serine phosphorylation (Ser 732) of FAK were essential for these effects. Semaphorin 3A and 3F mediate serine phosphorylation of FAK through the activation of Cdk5. Silencing of either Cdk5 or FAK in newborn neurons phenocopied the defects in dendritic development seen upon silencing of NRP1 or NRP2. Furthermore, in vivo overexpression of Cdk5 or FAK rescued the dendritic phenotypes seen in NRP1 and NRP2 deficient neurons. These results point to a novel role for class 3 semaphorins in promoting dendritic growth and branching during adult hippocampal neurogenesis through the activation of Cdk5-FAK signaling pathway.
Highlights
Active neurogenesis in mammals occurs throughout life in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus [1,2]
To determine the role of Sema3A/NRP1 and semaphorin 3F (Sema3F)/NRP2 signaling in adult neurogenesis, we employed a retrovirus-mediated method for birthdating and genetic manipulation of individual newborn neurons in the adult mouse dentate gyrus
We show Sema3A/NRP1 and Sema3F/NRP2 play an important role in dendritic development in newborn neurons in adult hippocampus
Summary
Active neurogenesis in mammals occurs throughout life in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus [1,2]. While it is well known that these external factors play important roles in proliferation, maintenance and survival of neural progenitors in the neurogenic niches, there remains a paucity of studies on how extrinsic factors shape intricate dendritic and axonal branching patterns that are critical for functional integration into existing adult neural networks. It is an intriguing and untested possibility that classical embryonic guidance cues can be co-opted for targeting and synaptic connections made by neurons born in the adult life. They were demonstrated to have both attractive and repulsive effects in various systems [10]
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