Abstract
Hippocampal volumes are smaller in psychiatric disorder patients and lower levels of hippocampal neurogenesis are the hypothesized cause. Understanding which molecular processes regulate hippocampal progenitor differentiation might aid in the identification of novel drug targets that can promote larger hippocampal volumes. Here we use a unique human cell line to assay genome-wide expression changes when hippocampal progenitor cells differentiate. RNA was extracted from proliferating cells versus differentiated neural cells and applied to Illumina Human HT-12 v4 Expression BeadChips. Linear regressions were used to determine the effect of differentiation on probe expression and we assessed enrichment for gene ontology (GO) terms. Genetic pathway analysis (MAGMA) was used to evaluate the relationship between hippocampal progenitor cell differentiation and adult hippocampal volume, using results from the imaging genomics consortium, ENIGMA. Downregulated transcripts were enriched for mitotic processes and upregulated transcripts were enriched for cell differentiation. Upregulated (differentiation) transcripts specifically, were also predictive of adult hippocampal volume; with Early growth response protein 2 identified as a hub transcription factor within the top GO term, and a potential drug target. Our results suggest that genes governing differentiation, rather than mitosis, have an impact on adult hippocampal volume and that these genes represent important drug targets.
Highlights
The specialisation of pluripotent stem cells into neurons, commonly referred to as “neurogenesis”, occurs across all brain regions during foetal development[1]
This study is the first to investigate the genome-wide expression changes which occur during human hippocampal progenitor cell differentiation as part of a 7-day protocol, Fig. 1
Top expression changes included functionally relevant genes, such as Transforming Growth Factor, Beta-Induced (TGFBI), Figs 3–4, which codes for a protein that increases in response to TGFB34
Summary
The specialisation of pluripotent stem cells into neurons, commonly referred to as “neurogenesis”, occurs across all brain regions during foetal development[1]. Previous work in non-human animal in vivo and in vitro systems have revealed substantial gene expression changes associated with neuronal differentiation, with Notch[16], Wnt[17,18,19] and brain derived neurotrophic factor (BDNF)[20,21] signalling pathways hypothesized to be key regulators. It’s unclear whether the pathways previously implicated for neuronal differentiation are important in regulating early hippocampal neural stem cell differentiation. It’s unclear what other transcriptional mechanisms might be important in regulating neural stem cell differentiation in the hippocampus in humans, in a hypothesis-free manner. The ultimate aim was to identify druggable genes and/or gene networks capable of promoting neural progenitor differentiation and larger hippocampal volumes
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