Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis.

S R Ferrón,I Sandovici,A Ward,T R Menheniott,A Ramme,E J Radford,A Domingo-Muelas,I Kleine,D Gray,M Constancia,A C Ferguson-Smith

doi:10.1038/ncomms9265

S R Ferrón, I Sandovici + Show 9 more

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https://doi.org/10.1038/ncomms9265

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Abstract

Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Here we address the importance of Igf2 imprinting for murine adult neurogenesis in the subventricular zone (SVZ) and in the subgranular zone (SGZ) of the hippocampus in vivo. In the SVZ, paracrine IGF2 is a cerebrospinal fluid and endothelial-derived neurogenic factor requiring biallelic expression, with mutants having reduced activation of the stem cell pool and impaired olfactory bulb neurogenesis. In contrast, Igf2 is imprinted in the hippocampus acting as an autocrine factor expressed in neural stem cells (NSCs) solely from the paternal allele. Conditional mutagenesis of Igf2 in blood vessels confirms that endothelial-derived IGF2 contributes to NSC maintenance in SVZ but not in the SGZ, and that this is regulated by the biallelic expression of IGF2 in the vascular compartment. Our findings indicate that a regulatory decision to imprint or not is a functionally important mechanism of transcriptional dosage control in adult neurogenesis.

Highlights

Genomic imprinting is implicated in the control of gene dosage in neurogenic niches
We recently found that selective biallelic expression of another paternally expressed imprinted gene, Dlk[1], in the subventricular zone (SVZ) is required for normal postnatal neurogenesis[38], suggesting that selective brain-specific modulation of imprinting at other loci, such as Igf[2], may have a significant role in neurogenesis
We demonstrate that the physiological temporal and region-specific modulation of Igf[2] imprinting plays a key role in regulating neural stem cells (NSCs) in the adult SVZ and subgranular zone (SGZ) neurogenic niches

Summary

Introduction

Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Here we address the importance of Igf[2] imprinting for murine adult neurogenesis in the subventricular zone (SVZ) and in the subgranular zone (SGZ) of the hippocampus in vivo. Dividing stem cells in the SGZ are in close proximity to an extensive network of interconnected blood vessels and parenchymal astrocytes that can regulate their proliferation and differentiation via paracrine signalling[4]. The ventricles contain cerebrospinal fluid (CSF) enriched with proteins secreted by the choroid plexus (CP) and brain vasculature Many of these blood vessel and CSF-derived molecules are known to regulate progenitor cell proliferation during embryonic brain development, including fibroblast growth factors (FGFs), sonic hedgehog, bone morphogenic proteins, retinoic acid, Wnts and insulin-like growth factors (IGFs)[14,15]. IGF2 has been suggested to influence the adult brain under pathological conditions, as the uncontrolled proliferation that is characteristic of glioblastoma has been linked to elevated CSF– IGF2 concentration[32] Together these studies implicate IGF2 as an important neurogenic regulator both during in utero development and in adult life

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