Temporal Analysis of Pituitary Transcriptional Dynamics in Mice Models of Hypopituitarism During Postnatal Development

Abstract

AbstractCongenital hypopituitarism is characterized by deficient pituitary hormone production, affecting growth and development. The molecular mechanisms underlying pituitary development and dysfunction in hypopituitarism remain incompletely understood. We investigated the expression of key pituitary development markers in three mouse models of congenital hypopituitarism, with molecular alterations in theProp1, Pou1f1, andαGSUgenes across critical postnatal developmental stages: neonatal (P0), early postnatal (P7), pubertal (4 weeks), and adult (8 weeks). We assessed mRNA and protein levels of the pituitary stem cell markers (SOX2), proliferation marker (Ki67) and pituitary hormones, correlating these with pituitary function and disease.Prop1deficiency led to significant upregulation ofSox2andHesx1during early postnatal development and in adulthood, diverging from the relatively stable expression patterns observed inPou1f1andαGSUmutants. Despite some variations, overallSox2andKi67expression profiles were similar betweenProp1andPou1f1mutants.Prop1mutants exhibited altered pituitary morphology, with increased SOX2-positive cells suggesting disrupted stem cell migration. During the pubertal period, a subset of hormone-producing cells inProp1mutants co-expressed SOX2, indicating differentiation without restoring normal pituitary function. Hormone analysis revealed transient gonadotropin production and secretion during sexual maturation inProp1mutants, without recovery of the hypogonadal phenotype. Our study elucidates the complex transcriptional dynamics of pituitary development markers in mouse models of congenital hypopituitarism, highlighting the pivotal role ofProp1in regulating stem cell marker expression. The distinct transcriptional responses inProp1mutants during key developmental windows shed light on the mechanisms of pituitary dysgenesis and the persistent inability to fully recover pituitary function, despite transient hormonal changes during puberty. These insights contribute to a better understanding of pituitary development and dysfunction in congenital hypopituitarism.