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

Abstract

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.

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

“…Remarkably, we also found a matching enrichment in the lactotroph and somatotroph cells in the pituitary. A role for imprinted genes in pituitary function is well known [ 49 , 50 ], with pituitary abnormalities associated with imprinted disorders such as PWS [ 51 ] and recent sequencing work showing imprinted genes are amongst the highest expressed transcripts in the mature and developing pituitary [ 52 ]. Specific genes highly expressed here, such as Dlk1 and Nnat, have been shown to alter somatotroph phenotypes [ 53 , 54 ].…”

ImprintedDlk1dosage as a size determinant of the mammalian pituitary gland

“…Additional experiments, such as measurement of Dlk1 levels in Pou1f1 -deleted mice, or targeted deletion of the putative POU1F1 binding sites at the Dlk1 locus would be required to definitively establish this finding. The expression pattern of Dlk1 in the progenitor compartment mirrors that of other imprinted genes in the ‘Imprinted Growth Network, IGN’, such as Igf2 , Cdkn1c and Grb10 (Scagliotti et al 2021). These genes have been suggested to comprise the hub of a core pathway that regulates embryonic growth and is progressively deactivated in the perinatal period (Lui et al 2008; Varrault et al 2006).…”

“…Analyses of single cell and single nuclei RNA-seq data. Single-cell sequencing data from the mouse pituitary gland was downloaded from GEO using accession numbers GSE120410 (postnatal day 4, P4) and GSE142074 (postnatal day 49, P49) and analysed as previously described (Scagliotti et al 2021).…”

“…We recently reanalysed publicly-available single-cell sequencing (scRNA-seq) data of the mouse pituitary gland generated by the Camper lab (Cheung et al 2018), (Cheung and Camper 2020) in order to catalogue imprinted gene expression in the early postnatal (P4) and adult (P49) gland (Scagliotti, 2021). These data confirmed our immunohistochemical analyses (Figure 1D) of enriched expression of Dlk1 in somatotrophs, lactotrophs and thyrotrophs, as well as in a subset of Sox2-expressing stem cells (Figure 3C).…”

Organizational Effects of Estrogens and Androgens on Estrogen and Androgen Receptor Expression in Pituitary and Adrenal Glands in Adult Male and Female Rats

“…Indeed, ERα knockout mice showed decreased a PRL mRNA expression (Scully et al, 1997 ; Avtanski et al, 2014 ), an effect probably mediated by the interaction between ERα and the pituitary-specific transcription factor Pit-1 (Simmons et al, 1990 ). The somatotropic and lactotropic cells of the anterior pituitary originated from Pit-1 expressing progenitors (González-Parra et al, 1996 ; Scagliotti et al, 2021 ). Moreover, Pit-1 quantifications in the anterior pituitary at different postnatal days in male and female rats revealed sex differences within the first 10 days of age, with increased levels of Pit-1 mRNA in somatotrophs of males and increased levels of Pit-1 mRNA in lactotrophs of females (González-Parra et al, 1996 ).…”