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

Abstract Congenital 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 the Prop1, Pou1f1, and αGSU genes 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. Prop1 deficiency led to significant upregulation of Sox2 and Hesx1 during early postnatal development and in adulthood, diverging from the relatively stable expression patterns observed in Pou1f1 and αGSU mutants. Despite some variations, overall Sox2 and Ki67 expression profiles were similar between Prop1 and Pou1f1 mutants. Prop1 mutants exhibited altered pituitary morphology, with increased SOX2-positive cells suggesting disrupted stem cell migration. During the pubertal period, a subset of hormone-producing cells in Prop1 mutants co-expressed SOX2, indicating differentiation without restoring normal pituitary function. Hormone analysis revealed transient gonadotropin production and secretion during sexual maturation in Prop1 mutants, 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 of Prop1 in regulating stem cell marker expression. The distinct transcriptional responses in Prop1 mutants 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. Competing Interest Statement The authors have declared no competing interest. Abbreviations - SOX2 - SRY-box transcription factor 2 - SOX9 - SRY-box transcription factor 9 - SOX3 - SRY-box transcription factor 3 - S100β - S100 protein, beta polypeptide, neural - HES1 - Hairy and enhancer of split-1 - TLE - Transducin-like enhancer of split - HESX1 - Homeobox gene in embryonic stem cell 1 - OTX2 - Orthodenticle homeobox 2 - LHX3 - LIM homeobox 3 - PROP1 - PROP paired-like homeobox 1 - POU1F1 - POU class 1 homeobox 1 - NOTCH2 - Notch receptor 2 - CGA - Glycoprotein hormones, alpha polypeptide - Ki67 - Marker of proliferation Ki-67 - CTNNB1 - Catenin beta 1 - TSH - Thyroid-stimulating hormone - LH - Luteinizing hormone - FSH - Follicle-stimulating hormone - GH - Growth hormone - ACTH - Adrenocorticotropic hormone - PRL - Prolactin