Biology subjects

Higgs, M. J.

Publications and source records attributed to Higgs, M. J..

4 recordsLinked to original sources

bioRxiv2026

Prader-Willi syndrome genes are expressed in placenta and play a role in function

The neurodevelopmental disorder Prader-Willi syndrome (PWS) is caused by loss of paternally-derived gene expression from the imprinted interval on chromosome 15q11-q13. Recently, it has been suggested that the abnormal feeding-related behaviours characteristic of PWS may, in part, be developmentally programmed in utero via abnormal placental function. Here we report that several PWS-genes are expressed in mouse placenta with three PWS-transcripts Magel2, Necdin and the lncRNA Sngh14, co-localising to the Kdr-positive fetal endothelial cells of the labyrinth zone central to nutrient transport. In a novel PWS deletion mouse model (Large+/-) we find markedly reduced expression of PWS genes in the placenta and an associated [~]25% reduction in Kdr-positive fetal endothelial cells. Although this did not directly translate into a significant reduction in fetal growth late in gestation, these data suggest that placental function and nutrient transfer from mother to fetus could be compromised in PWS contributing to later post-natal phenotypes. Summary statementReduced expression of PWS-associated genes in the mouse placenta results in a 25% loss of the fetal endothelial cells that play a central role in nutrient and gas exchange.

physiology↗

bioRxiv2023

Tissue-wide scRNA-seq analysis reveals enrichment of imprinted genes in stem and endocrine cell-types in mice

Enriched expression of imprinted genes may provide evidence of convergent function. Here we interrogated five single-cell RNA sequencing datasets to identify imprinted gene over-representation in the embryonic and adult mouse focusing on tissues including the bladder, pancreas, mammary gland and muscle. We identify a consistent enrichment of imprinted genes in stromal cell and mesenchymal stem cell populations across these tissues, suggesting a role in tissue maintenance. Furthermore, we identify a distinct enrichment in the endocrine islets of the mouse pancreas, over and above the stromal/stem cells from this tissue. Taken together with our previous work examining imprinted gene expression in cell subpopulations of the adult mouse brain and pituitary gland, these data suggest that genomic imprinting influences physiology largely via separate systems of cell populations either involved in hormonal signalling or in stemness and cell-fate co-ordination.

genetics↗

bioRxiv2023

Parenting deficits in Magel2-null mice predicted from systematic investigation of imprinted gene expression in galanin neurons of the hypothalamus

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 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.

neuroscience↗

bioRxiv2020

Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution

BackgroundAlthough a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using thirteen single-cell RNA sequencing datasets we systematically investigated imprinted gene over-representation at the organ, brain region, and cell-specific levels. ResultsWe established that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examined brain-wide datasets to test enrichment within distinct brain regions and neuron subpopulations and demonstrated over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we identified hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression. ConclusionsThese analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted gene expression converges. Our findings indicate the neuronal regulation of motivated behaviours such as feeding and sleep, alongside the regulation of pituitary function as functional hotspots for imprinting, thus adding statistical rigour to prior assumptions and providing testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.

genetics↗