Gastric epithelial cells differentiate throughout the third postnatal week in rats, and become completely functional by weaning time. When suckling is interrupted by early weaning (EW), cell proliferation and differentiation change in the gastric mucosa, and regulatory mechanisms might involve corticosterone activity. Here we used EW and RU486 (glucocorticoid receptor antagonist) to investigate the roles of corticosterone on differentiation of mucous neck (MNC) and zymogenic cells (ZC) in rats, and to evaluate whether effects persisted in young adults. MNC give rise to ZC, and mucin 6, Mist1, pepsinogen a5 and pepsinogen C are produced to characterize these cells. We found that in pups, EW augmented the expression of mucins, Mist1 and pepsinogen C at mRNA and protein levels, and it changed the number of MNC and ZC. Corticosterone regulated pepsinogen C expression, and MNC and ZC distributions. Further, the changes on MNC population and pepsinogen C were maintained until early- adult life. Therefore, by using EW as a model for altered corticosterone activity in rats, we demonstrated that the differentiation of secretory epithelial cells is sensitive to the type of nutrient in the lumen. Moreover, this environmental perception activates corticosterone to change maturation and reprogram cellular functions in adulthood.

Neonatal- Maternal Separation (NMS) deprives mammals from breastfeeding and maternal care, influencing growth during suckling- weaning transition. In the gastric mucosa, Mist1 (encoded by Bhlha15 gene) and moesin organize the secretory apparatus for pepsinogen C in zymogenic cells. Our current hypothesis was that NMS would change corticosterone activity through receptors (GR), which would modify molecules involved in zymogenic cell differentiation in rats. We found that NMS increased corticosterone levels from 18 days onwards, as GR decreased in the gastric mucosa. However, as nuclear GR was detected, we investigated receptor binding to responsive elements (GRE) and observed an augment in NMS groups. Next, we demonstrated that NMS increased zymogenic population (18 and and 30 days), and targeted Mist1 and moesin. Finally, we searched for evolutionarily conserved sequences that contained GRE in genes involved in pepsinogen C secretion, and found that the genomic regions of Bhlha15 and PgC contained sites highly likely to be responsive to glucocorticoids. We suggest that NMS triggers GR- GRE to enhance the expression and to prime genes that organize cellular architecture in zymogenic population for PgC function. As pepsinogen C- pepsin is essential for digestion, disturbance of parenting through NMS might alter functions of gastric mucosa in a permanent manner.