Use of a prolactin-Cre/ROSA-YFP transgenic mouse provides no evidence for lactotroph transdifferentiation after weaning, or increase in lactotroph/somatotroph proportion in lactation

Abstract

In rats, a shift from somatotroph dominance to lactotroph dominance during pregnancy and lactation is well reported. Somatotroph to lactotroph transdifferentiation and increased lactotroph mitotic activity are believed to account for this and associated pituitary hypertrophy. A combination of cell death and transdifferentiation away from the lactotroph phenotype has been reported to restore non-pregnant pituitary proportions after weaning. To attempt to confirm that a similar process occurs in mice, we generated and used a transgenic reporter mouse model (prolactin (PRL)-Cre/ROSA26-expression of yellow fluorescent protein (EYFP)) in which PRL promoter activity at any time resulted in permanent, stable, and highly specific EYFP. Triple immunochemistry for GH, PRL, and EYFP was used to quantify EYFP+ve, PRL−ve, and GH+ve cell populations during pregnancy and lactation, and for up to 3 weeks after weaning, and concurrent changes in cell size were estimated. At all stages, the EYFP reporter was expressed in 80% of the lactotrophs, but in fewer than 1% of other pituitary cell types, indicating that transdifferentiation from those lactotrophs where reporter expression was activated is extremely rare. Contrary to expectations, no increase in the lactotroph/somatotroph ratio was seen during pregnancy and lactation, whether assessed by immunochemistry for the reporter or PRL: findings confirmed by PRL immunochemistry in non-transgenic mice. Mammosomatotrophs were rarely encountered at the age group studied. Individual EYFP+ve cell volumes increased significantly by mid-lactation compared with virgin animals. This, in combination with a modest and non-cell type-specific estrogen-induced increase in mitotic activity, could account for pregnancy-induced changes in overall pituitary size.

Increased Wingless ( Wnt ) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans

“…Ctnnb1 +/lox(ex3) , Hesx1-Cre, Prl-Cre, R26-YFP, and BAT-gal mice have been described previously (25,26,29,34,38). The Pit1-Cre and Gh-Cre transgenic lines were generated by M. Treier [European Molecular Biology Laboratory (Heidelberg)].…”

“…Transgenic mice expressing Cre recombinase under the control of the Pit1, Gh, and Prolactin (Prl) promoters were crossed with the Ctnnb1 lox(ex3)/lox(ex3) mice to drive expression of mutant β-catenin in Pit1-committed progenitors and differentiated hormone-producing cells (Fig. S8) (34). Gh-Cre;Ctnnb1 +/lox(ex3) , Prl-Cre;Ctnnb1 +/lox(ex3)…”

Plasticity of the Prolactin (PRL) Axis: Mechanisms Underlying Regulation of Output in Female Mice

“…Estradiol [59], along with a range of paracrine factors [60], control lactotroph proliferation in the adult gland but in combination with DA the steroid also regulates lactotroph apoptosis [61]. Trans-differentiation of other pituitary cell types to lactotrophs has also been described as a mechanism regulating their number [62], although recent studies suggest this is unlikely to have an important role in mice [63].…”

Adult Pituitary Stem Cells: From Pituitary Plasticity to Adenoma Development

“…In fact, mitotic events observed during adrenalectomy mainly involve hormonally null cells (>90%) that only after few weeks differentiate into corticotropes [for review see, [10,11]]. Similarly, genetic lineage trace experiments suggested that new prolactin-secreting cells, developed in response to estrogens (for example during pregnancy), are rarely derived from differentiated somatotrope cells [12], but are mainly derived from a self-limiting wave of proliferation of the non-hormonal pool of pituitary cells [6]. All this evidence led to the hypothesis that both basal pituitary cell turnover and cellular changes occurring as dynamic adaptation in physiological or pathological conditions could be driven by the recruitment of a still unidentified, small pituitary cell subpopulation endowed with stem/progenitor cell characteristics [9].…”