Discovering the Downstream Targets of Follistatin Responsible for Adult Neurogenesis and Learning Behaviour

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Evidence for the presence of adult neurogenesis was first discovered over 50 years ago. However, the genetic factors which influence neurogenesis remain to be extensively studied. In this study, we used a high resolution method for identifying loci associated with neurogenesis by combining genetic mapping with sequencing information. We identified a candidate gene, follistatin (Fst), for further study due to its strong expression in the dentate gyrus. Mice deficient in brain based Fst expression feature impaired spatial learning and hippocampal neurogenesis. In future experiments, to avoid the influence of this gene in development, we will conduct the behaviour and neurogenesis experiments in Fst inducible KO mice. Additionally, to understand the impact of FST on hippocampal electrical properties, we will study long term potentiation in Fst inducible KO mice. To better understand the importance of hippocampal FST, we will inject AAV9.CMV.Cre viral vector into the hippocampi of Fst floxed mice to eliminate Fst expression. We will then measure neurogenesis and learning behaviour and compare to floxed mice with control viral vector injections. Next, to examine whether the phenotypes we detected in KO mice can be rescued by increasing Fst expression, we will inject AAV9.CAG.Fst viral vector into the hippocampi of KO mice and subsequently assess hippocampal morphology and behaviour. For the last part of this project, we will seek to find the possible pathway and mechanism whereby Fst mediates neurogenesis and spatial learning. We will do this through two different approaches. The first approach will utilise RNA-seq to identify differential hippocampal gene expression between WT and KO mice, and we will subsequently use Weighted Gene Co-Expression Network Analysis to find the network and linkage of candidate genes. For the second approach we will use co-immunoprecipitation and mass spectrometry to identify the targets that follistatin bind to in the hippocampus. Information from RNA-seq technology and proteomic analysis shall give us a better understanding of how FST interacts with its targets and influences the downstream expression profile.

Project IDs

Project ID:PC10508-0355
External Project ID:MOST105-2320-B182-040
StatusFinished
Effective start/end date01/08/1631/07/17

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