The parenting hub of the hypothalamus is a focus of imprinted gene action.

Imprinted genes are subject to germline epigenetic modification resulting in parental-specific allelic silencing. Although genomic imprinting is thought to be important for maternal behaviour, this idea is based on serendipitous findings from a small number of imprinted genes. Here, we undertook an unbiased systems biology approach, taking advantage of the recent delineation of specific neuronal populations responsible for controlling parental care, to test whether imprinted genes significantly converge to regulate parenting behaviour. Using single-cell RNA sequencing datasets, we identified a specific enrichment of imprinted gene expression in a recognised "parenting hub", the galanin-expressing neurons of the preoptic area. We tested the validity of linking enriched expression in these neurons to function by focusing on MAGE family member L2 (Magel2), an imprinted gene not previously linked to parenting behaviour. We confirmed expression of Magel2 in the preoptic area galanin expressing neurons. We then examined the parenting behaviour of Magel2-null(+/p) mice. Magel2-null mothers, fathers and virgin females demonstrated deficits in pup retrieval, nest building and pup-directed motivation, identifying a central role for this gene in parenting. Finally, we show that Magel2-null mothers and fathers have a significant reduction in POA galanin expressing cells, which in turn contributes to a reduced c-Fos response in the POA upon exposure to pups. Our findings identify a novel imprinted gene that impacts parenting behaviour and, moreover, demonstrates the utility of using single-cell RNA sequencing data to predict gene function from expression and in doing so here, have identified a purposeful role for genomic imprinting in mediating parental behaviour. Author summary: Genomic imprinting is a fascinating phenomenon that affects a small sub-group of the approximately 22,000 found in mammals. Unlike most genes that are equally expressed from both inherited parental copies (or alleles), so called imprinted genes are only expressed from one inherited allele, and this is usually fixed so that some imprinted genes are only active from the maternal copy, whereas others are only active from the paternal copy. This silencing of one of the parental copies makes genomic imprinting and evolutionary conundrum and the best way to understand why imprinted genes exist is to investigate the physiologies upon which they impact. Here we investigated imprinted gene expression in the brain circuitry that controls parental behaviours in mammals. We show that as a group the imprinted genes are disproportionately represented in the gene expression profile of the key neurons in this circuitry. We then tested this approach by showing that loss expression of a gene called Magel2 that was one of those imprinted genes identified in this brain circuitry, leads to deficits in parental behaviour in mice. Taken together with previous work, our findings indicate that genomic imprinting plays a particularly important role in the control of parenting behaviour. [ABSTRACT FROM AUTHOR]