Imprinted genes influencing the quality of maternal care

Creeth, Hugo; McNamara, Gráinne; Isles, Anthony R; Roshan, John

doi:10.1016/j.yfrne.2018.12.003

Cited by 23 publications

(14 citation statements)

References 126 publications

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“…When opposite sexes share a cage, they accosionally mate successfully and produce normal sized litters. But they lose a large part of these litters, apparently due to lack of maternal care, which is a phenotype that was also found for three other imprinted loci (2,29).…”

Section: Discussionsupporting

confidence: 52%

The imprinted lncRNA Peg13 regulates sexual preference and the gender-specific brain transcriptome in mice

Keshavarz

Tautz

2020

Preprint

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Mammalian genomes include many maternally or paternally imprinted genes. Most of these are also expressed in the brain and several were previously implicated in regulating specific behavioral traits. We have used here a knockout approach to study the function of Peg13. Peg13 codes for a fast evolving lncRNA and is part of a complex of imprinted genes on chromosome 15 in the mouse and chromosome 8 in humans. Two knockout constructs were analyzed, one with a full deletion of the gene, the other with a deletion of the three prime-half. The full deletion is semi lethal, while the partial deletion is fully viable, but the mice show distinctive behavioral differences. They lose interest in the opposite sex and show instead a preference for wildtype animals of the same sex. Further, they show a higher level of anxiety, as well as lowered activity and curiosity and females have a deficiency in pup retrieval behavior. Brain RNA expression analysis reveals that genes involved in the serotonergic system, formation of glutamergic synapses, olfactory processing and estrogen signaling, as well as more than half of the other known imprinted genes are affected in Peg13 deficient mice. Intriguingly, the pathways are differentially affected in the sexes, with the result that the male and female brains of Peg13 deficient mice differ more from each other than those of wildtype mice. We conclude that Peg13 is part of a developmental pathway that regulates the neurobiology of social interactions.

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Section: Discussionsupporting

confidence: 52%

The imprinted lncRNA Peg13 regulates sexual preference and the gender-specific brain transcriptome in mice

Keshavarz

Tautz

2020

Preprint

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“…In rodents, maternal adaptations during pregnancy include changes in behaviour such as increased appetite, increased anxiety and altered nest building and grooming. The greatest changes take place after birth with mothers focused on nurturing their offspring, providing food, warmth, shelter and protection [13]. Both virgin females and male rodents can assume parental behaviour but this response requires several days of exposure to the pups in order to be initiated.…”

Section: Maternal Behaviourmentioning

confidence: 99%

“…The presence of pups is important for the manifestation of maternal behaviour and any mutation impacting pup characteristics has the potential to result in a secondary effect on maternal behaviour [13,72]. From birth pups begin communicating to their mothers using clicks and whistles.…”

Section: Impact Of Different Doses Of Phlda2 In the Placenta On The Behaviour Of Wild Type Damsmentioning

confidence: 99%

The placental programming hypothesis: Placental endocrine insufficiency and the co-occurrence of low birth weight and maternal mood disorders

Creeth

Roshan

2020

Placenta

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Polypeptide hormones and steroid hormones, either expressed by the placenta or dependant on the placenta for their synthesis, are key to driving adaptations in the mother during pregnancy that support growth in utero. These adaptations include changes in maternal behaviour that take place in pregnancy and after the birth to ensure that offspring receive appropriate care and nutrition. Placentally-derived hormones implicated in the programming of maternal caregiving in rodents include prolactin-related hormones and steroid hormones.Neuromodulators produced by the placenta may act directly on the fetus to support brain development. A number of imprinted genes function antagonistically in the placenta to regulate the development of key placental endocrine lineages expressing these hormones. Gain-inexpression of the normally maternally expressed gene Phlda2 or loss-of-function of the normally paternally expressed gene Peg3 results in fewer endocrine cells in the placenta, and pups are born low birth weight. Importantly, wild type dams carrying these genetically altered pups display alterations in their behaviour with decreased focus on nurturing (Phlda2) or heightened anxiety (Peg3). These same genes may regulate placental hormones in human pregnancies, with the potential to influence birth weight and maternal mood. Consequently, the aberrant expression of imprinted genes in the placenta may underlie the reported cooccurrence of low birth weight with maternal prenatal depression. Key word: Placental endocrine insufficiency, imprinted genes, hormones, maternal behaviour, low birth weight, depression Placental hormones implicated in the induction of maternal behaviourKey hormones involved in pregnancy-associated behaviours are the lactogenic hormones pituitary prolactin and prolactin-related hormones manufactured by the placenta, sometimes referred to as placental lactogens (see later). Prolactin is secreted from the pituitary to act locally on the maternal brain whereas the placentally-derived lactogenic hormones are thought to gain access to the maternal brain via the cerebrospinal fluid [14]. Key studies in rodents have experimentally demonstrated the importance of lactogenic signalling for maternal behaviour. These studies involved the infusion of prolactin or placental lactogen directly into the brains of non-pregnant animals which resulted in the stimulation of aspects postpartum maternal behaviour such as pup retrieval [14][15][16][17][18][19]. Conversely, experimentally-induced low levels of prolactin in pregnancy have been linked to increased postpartum anxiety and decreased pup retrieval [20]. Lactogenic hormones are thought to mediate their activity, at least in part, via the maternal prolactin receptor (Prlr) [21]. Loss of function of Prlr in mice was shown to result in a deficit in maternal behaviour [22,23] and, more precisely, loss of function of Prlr restricted to the medial preoptic area of the brain [24]. Signalling via Prlr is also required for the pregnancy-related increases in neurogenesis that tak...

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“…As well as directly influencing embryonic and placental growth pathways, it is now well recognised that imprinted genes can influence gestational hormone production. Notably, imprinted gene dosage manipulation in the mouse can alter the size and activity of the placental endocrine compartment to influence the production of placental lactogens (reviewed in [ 116 ]), and foetal production of DLK1 promotes maximal maternal GH levels circulating in pregnancy [ 114 ]. Despite this, little attention has been paid to how imprinted genes might act in the mother to influence her sensitivity to endocrine manipulation by the conceptus.…”

Section: Introductionmentioning

confidence: 99%

“…There is some evidence that such a mechanism may be occurring during the lactation period, since dams lacking a functional maternal allele of growth factor receptor-bound protein 10 ( Grb10 ), exhibit PRL resistance [ 117 ]. In addition, several imprinted gene knock-outs in mice influence latency to adopt maternal behaviour, a trait partially controlled by PRL signalling [ 109 , 116 ].…”

Section: Introductionmentioning

confidence: 99%

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

Scagliotti

Esse

Willis

et al. 2021

Genes

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In mammals, imprinted genes regulate many critical endocrine processes such as growth, the onset of puberty and maternal reproductive behaviour. Human imprinting disorders (IDs) are caused by genetic and epigenetic mechanisms that alter the expression dosage of imprinted genes. Due to improvements in diagnosis, increasing numbers of patients with IDs are now identified and monitored across their lifetimes. Seminal work has revealed that IDs have a strong endocrine component, yet the contribution of imprinted gene products in the development and function of the hypothalamo-pituitary axis are not well defined. Postnatal endocrine processes are dependent upon the production of hormones from the pituitary gland. While the actions of a few imprinted genes in pituitary development and function have been described, to date there has been no attempt to link the expression of these genes as a class to the formation and function of this essential organ. This is important because IDs show considerable overlap, and imprinted genes are known to define a transcriptional network related to organ growth. This knowledge deficit is partly due to technical difficulties in obtaining useful transcriptomic data from the pituitary gland, namely, its small size during development and cellular complexity in maturity. Here we utilise high-sensitivity RNA sequencing at the embryonic stages, and single-cell RNA sequencing data to describe the imprinted transcriptome of the pituitary gland. In concert, we provide a comprehensive literature review of the current knowledge of the role of imprinted genes in pituitary hormonal pathways and how these relate to IDs. We present new data that implicate imprinted gene networks in the development of the gland and in the stem cell compartment. Furthermore, we suggest novel roles for individual imprinted genes in the aetiology of IDs. Finally, we describe the dynamic regulation of imprinted genes in the pituitary gland of the pregnant mother, with implications for the regulation of maternal metabolic adaptations to pregnancy.

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Imprinted genes influencing the quality of maternal care

Cited by 23 publications

References 126 publications

The imprinted lncRNA Peg13 regulates sexual preference and the gender-specific brain transcriptome in mice

The imprinted lncRNA Peg13 regulates sexual preference and the gender-specific brain transcriptome in mice

The placental programming hypothesis: Placental endocrine insufficiency and the co-occurrence of low birth weight and maternal mood disorders

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

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