ESPE Yearbook of Paediatric Endocrinology

Hum Mol Genet 34(10) (2025) 870-881.PMID: 40044116

Brief Summary: This experimental study sheds new light on the critical role of Nucleoredoxin (Nxn) in orchestrating WNT signalling during pituitary stem cell differentiation. Nxn, a redox-sensitive oxidoreductase, had previously been linked to broader developmental syndromes, such as Robinow syndrome.

The authors used RNAscope to show strong Nxn expression in Rathke’s pouch, infundibulum, ventral diencephalon, and co-expression with Sox2⁺ stem/progenitor cell populations, positioning Nxn at critical sites for pituitary lineage decisions. Moreover, phenotypic analyses of Nxn^−/− embryos demonstrated dysmorphic features such as cleft palate and pituitary abnormalities from e11.5 onward, basisphenoid bone ossification defects. These phenotypes are reminiscent of human Robinow syndrome. The authors used single-cell mRNA-seq at e14.5; this uncovered reduced non-canonical WNT5A signalling and a shift in pseudotime trajectories. Stem/progenitor cells accumulated, while differentiated thyrotropes and other lineages were depleted. The data suggests a model where Nxn regulates non-canonical WNT singalling, to enable stem-to-lineage transitions in the pituitary, likely through redox modulation of WNT components such as DVL.

This is work places NXN as a pivotal factor in enabling stem cells to exit an undifferentiated state, implicating redox-regulated WNT cues in early pituitary cell fate decisions. Given that human NXN mutations cause recessive Robinow syndrome (characterized by skeletal and craniofacial malformations), these findings suggest endocrine evaluation is warranted for patients, particularly regarding pituitary structure and hormone status. It will be valuable to confirm these mouse findings in humans, by examining anterior pituitary function in Robinow patients with NXN mutations.

Overall, this is a compelling, methodologically rigorous study that addresses fundamental questions in pituitary development while offering translational value for human disorders. It opens avenues for deeper investigation into redox regulation of WNT and for potential endocrine evaluation in related congenital syndromes such as Robinow syndrome.