Brinkmeier, M. | bioRxiv Science

bioRxiv2026

PRC2 complex subunit JARID2 regulates embryonic pituitary stem cell differentiation to the POMC lineage

The pituitary is essential for growth, fertility, and stress response. Pituitary development is defined by transcription factor cascades, but how chromatin landscapes influence it remains elusive. JARID2 is a subunit of polycomb repressive complex 2 repressing transcription by depositing trimethylation on histone 3 lysine 27 (H3K27me3). Here, we established that H3K27me3 levels increase with differentiation in anterior pituitary from embryonic day (E) 10.5 to E14.5 despite ubiquitous Jarid2 mRNA expression. Germline loss of Jarid2 causes pituitary stem cell (PSC) hyperplasia and corticotrope hypoplasia without changing H3K27me3 bulk levels at E14.5. Pituitary-specific loss of Jarid2 with Prop1T2AiCre (Jarid2Pitko/Pitko) exhibits POMC lineage hypoplasia and PSC hyperplasia at E16.5. Pou1f1 or Nr5a1 lineages are not affected by Jarid2 mutation. To determine gene expression and chromatin accessibility changes in Jarid2Pitko/Pitko, we performed single nucleus (sn) multi-omics on E14.5 pituitaries. SnRNAseq revealed potential targets of Jarid2, including Meis2. SnATACseq revealed chromatin reprograming towards PSC retention rather than differentiation. Pax7 is reduced in both modalities in PSC. Together, we show that Jarid2 promotes stemness exit and POMC lineage differentiation, uncovering novel epigenetic regulation of pituitary development. SUMMARY STATEMENTExpanding the repertoire of the regulation of pituitary development, chromatin modifier also help stem cells in this essential gland to differentiate and choose hormone-secreting fate.

Developmental Biology↗

bioRxiv2025

Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation

Nucleoredoxin (Nxn) encodes a multi-functional enzyme with oxidoreductase activity that regulates many different signaling pathways and cellular processes in a redox-dependent manner. Rare NXN mutations are reported in individuals with recessive Robinow syndrome, which involves mesomelic skeletal dysplasia, short stature, craniofacial dysmorphisms, and incompletely penetrant heart and palate defects. Here we report that Nxn is expressed in the ventral diencephalon and developing pituitary gland, and that Nxn deficient mice have pituitary dysmorphology and craniofacial abnormalities that include defects in the skull base and cleft palate. Nxn mutant mice exhibit reduced WNT signaling and reduced differentiation of pituitary stem cells into hormone-producing cells. These results suggest patients with Robinow syndrome could benefit from evaluation by endocrinologists for pituitary structural imaging and hormone insufficiency. HighlightsNxn deficiency causes neonatal lethality, cleft palate, craniofacial abnormalities, and other structural birth defects. Nxn deficiency causes pituitary dysmorphology. Analysis of scRNA seq reveals delayed trajectory during early pituitary cell differentiation. Nxn deficiency reduces canonical and non-canonical Wnt signaling in developing pituitary glands. Nxn deficiency reduces stem cell differentiation into pituitary hormone-producing cells.

developmental biology↗