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The pituitary gland is the master endocrine gland, harboring stem cells with various genetic characteristics; however, data from non-rodent and non-human sources are scarce. In this study, we isolated putative stem cells from the bovine pituitary gland and investigated their potential for differentiation into hormone-producing cells. Immunohistochemical analysis revealed that in calves and heifers, stem cell marker sex-determining region Y-box 2 (SOX2)-positive cells were widely present in the pituitary gland and partially co-localized with anterior pituitary hormones. Next, a single-cell suspension of primary anterior lobe cells from bovines aged 0 and 12 months was subjected to two-dimensional culture. Consequently, some cells proliferated in the culture dishes. The expression levels of Sox2 and several other stem cell markers were higher in these cells after culture. In addition, almost all proliferating cells were positive for SOX2, whereas all were negative for hormones. In three-dimensional cultures, SOX2-positive cells presented a spheroid-like morphology and differentiated into endocrine cells. These results provide evidence that SOX2-positive cells are pituitary stem cells with the potential to differentiate into hormone-producing cells, regardless of age. Our data lay a theoretical foundation for further studies on controlling fundamental processes, such as body growth, reproduction, and lactation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mammalian genomes contain thousands of genes for long noncoding RNA (lncRNAs), some of which have been shown to affect protein coding gene expression through diverse mechanisms. The lncRNA transcripts are longer than 200 nucleotides and are often capped, spliced, and polyadenylated, but not translated into protein. Nuclear lncRNAs can modify chromatin structure and transcription in trans or cis by interacting with the DNA, forming R-loops, and recruiting regulatory proteins. Not much is known about the role of lncRNA in pituitary gland differentiation and function. We mined transcriptome data from mouse pituitary glands collected at embryonic days 12.5 and 14.5 and identified over 200 different lncRNA transcripts. To develop a research resource for the study of lncRNA, we used pituitary cre transgenes to tag pituitary cell types in adult mice with fluorescent markers, and enriched for thyrotropes, gonadotropes, and somatotropes using fluorescence-activated cell sorting. We determined the transcriptome of each cell population using RNA sequencing and mined the data for lncRNA. We detected hundreds of lncRNAs in adult pituitary cells; a few were located immediately nearby genes that encode pituitary hormones or lineage-specific transcription factors. The location of these lncRNAs suggests the possibility of a cis-acting regulatory role in pituitary development or function, and we observe coordinated expression of 2 of them with their putative target genes in transgenic mice. This research resource sets the foundation for examining the actions of lncRNAs on their putative target genes and determining whether they have roles during development and in response to physiological demand., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Organ architecture is established during development through intricate cell-cell communication mechanisms, yet the specific signals mediating these communications often remain elusive. Here, we used the anterior pituitary gland that harbors different interdigitated hormone-secreting homotypic cell networks to dissect cell-cell communication mechanisms operating during late development. We show that blocking differentiation of corticotrope cells leads to pituitary hypoplasia with a major effect on somatotrope cells that directly contact corticotropes. Gene knockout of the corticotrope-restricted transcription factor Tpit results in fewer somatotropes, with less secretory granules and a loss of cell polarity, resulting in systemic growth retardation. Single-cell transcriptomic analyses identified FGF1 as a corticotrope-specific Tpit dosage-dependent target gene responsible for these phenotypes. Consistently, genetic ablation of FGF1 in mice phenocopies pituitary hypoplasia and growth impairment observed in Tpit -deficient mice. These findings reveal FGF1 produced by the corticotrope cell network as an essential paracrine signaling molecule participating in pituitary architecture and size., Competing Interests: Competing interests statement:The authors declare no competing interest.

Gonadotropin-releasing hormone (GnRH) is a key stimulator for gonadotropin secretion in the pituitary and its pivotal role in reproduction is well conserved in vertebrates. In fish models, GnRH can also induce prolactin (PRL) release, but little is known for the corresponding effect on PRL gene expression as well as the post-receptor signalling involved. Using grass carp as a model, the functional role of GnRH and its underlying signal transduction for PRL regulation were examined at the pituitary level. Using laser capture microdissection coupled with RT-PCR, GnRH receptor expression could be located in carp lactotrophs. In primary cell culture prepared from grass carp pituitaries, the native forms of GnRH, GnRH2 and GnRH3, as well as the GnRH agonist [D-Arg 6 , Pro 9 , NEt]-sGnRH were all effective in elevating PRL secretion, PRL mRNA level, PRL cell content and total production. In pituitary cells prepared from the rostral pars distalis, the region in the carp pituitary enriched with lactotrophs, GnRH not only increased cAMP synthesis with parallel CREB phosphorylation and nuclear translocation but also induced a rapid rise in cytosolic Ca 2+ by Ca 2+ influx via L-type voltage-sensitive Ca 2+ channel (VSCC) with subsequent CaM expression and NFAT 2 dephosphorylation. In carp pituitary cells prepared from whole pituitaries, GnRH-induced PRL secretion was reduced/negated by inhibiting cAMP/PKA, PLC/PKC and Ca 2+ /CaM/CaMK-II pathways but not the signalling events via IP 3 and CaN/NFAT. The corresponding effect on PRL mRNA expression, however, was blocked by inhibiting cAMP/PKA/CREB/CBP and Ca 2+ /CaM/CaN/NFAT 2 signalling but not PLC/IP 3 /PKC pathway. At the pituitary cell level, activation of cAMP/PKA pathway could also induce CaM expression and Ca 2+ influx via VSCC with parallel rises in PRL release and gene expression in a Ca 2+ /CaM-dependent manner. These findings, as a whole, suggest that the cAMP/PKA-, PLC/PKC- and Ca 2+ /CaM-dependent cascades are differentially involved in GnRH-induced PRL secretion and PRL transcript expression in carp lactotrophs. During the process, a functional crosstalk between the cAMP/PKA- and Ca 2+ /CaM-dependent pathways may occur with PRL release linked with CaMK-II and PKC activation and PRL gene transcription caused by nuclear action of CREB/CBP and CaN/NFAT 2 signalling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Li, Ye, He, Ko, Cheng, Chan and Wong.)

The anterior pituitary plays a critical role in the endocrine system, contains gonadotrophs, which regulate reproductive efficiency by secreting follicle-stimulating hormone (FSH) and luteinizing hormone (LH). PPP2R2A is a serine-threonine phosphatase that regulates reproductive functions in both females and males, its function in pituitary cells remain unclear. Hu sheep is a highly prolific breed, which makes it suitable for studying reproductive mechanisms. In this study, the relative abundances of PPP2R2A mRNA expression were higher in the pituitary of high-prolificacy (HF) Hu sheep compared to those of low-prolificacy (LF) Hu sheep. Additionally, we demonstrated that PPP2R2A promotes pituitary cell proliferation and gonadotropin secretion using the EdU assay and ELISA, respectively. Moreover, it inhibits pituitary cell apoptosis using flow cytometry. Furthermore, PPP2R2A may affect pituitary cell function by regulating the AKT/mTOR signaling pathway. In summary, our findings suggest that PPP2R2A may play a role in regulating pituitary function and influencing the secretion of gonadotropins., Competing Interests: Declaration of Competing Interest The authors do not have competing interests that interfere with the independence and rigor of these studies., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuregulin-4 (Nrg4) and melatonin play vital roles in endocrine diseases. However, there is little discussion about the function and potential mechanism of Nrg4 and melatonin in prolactin (PRL) regulation. The human normal pituitary data from Gene Expression Profiling Interactive Analysis (GEPIA) database was used to explore the correlation between NRG4 and PRL. The expression and correlation of NRG4 and PRL were determined by Immunofluorescence staining (IF) and human normal pituitary tissue microarray. Western Blot (WB) was used to detect the expression of PRL, p-ErbB2/3/4, ErbB2/3/4, p-Erk1/2, Erk1/2, p-Akt and Akt in PRL-secreting pituitary GH3 and RC-4B/C cells treated by Nrg4, Nrg4-small interfering RNA, Erk1/2 inhibitor FR180204 and melatonin. The expression of NRG4 was significantly positively correlated with that of PRL in the GEPIA database and normal human pituitary tissues. Nrg4 significantly increased the expression and secretion of PRL and p-Erk1/2 expression in GH3 cells and RC-4B/C cells. Inhibition of Nrg4 significantly inhibited PRL expression. The increased levels of p-Erk1/2 and PRL induced by Nrg4 were abolished significantly in response to FR180204 in GH3 and RC-4B/C cells. Additionally, Melatonin promotes the expression of Nrg4, p-ErbB4, p-Erk1/2, and PRL and can further promote the expression of p-Erk1/2 and PRL in combination with Nrg4. Further investigation into the function of Nrg4 and melatonin on PRL expression and secretion may provide new clues to advance the clinical control of prolactinomas and hyperprolactinemia., (© 2024 Wiley Periodicals LLC.)