Preprint reveals sex-specific neurodevelopmental phenotypes in Down syndrome mouse model and tests neonatal DYRK1A reduction

A preprint posted to bioRxiv reports sex-specific developmental phenotypes in Ts65Dn mice, a widely used model of Down syndrome (DS; trisomy 21), and examines whether neonatal reduction of DYRK1A activity differentially affects male and female animals. DYRK1A (Dual-specificity tyrosine phosphorylation-regulated kinase 1A) is encoded on human chromosome 21 and is overexpressed in individuals with trisomy 21; it has been identified as a candidate therapeutic target for the cognitive and neurodevelopmental features of DS.

Ts65Dn pups of both sexes are trisomic for approximately 100 human chromosome 21 orthologues including Dyrk1a, and the preprint reports that both sexes show significant DYRK1A overexpression in the hippocampus at postnatal day 6. Despite this shared molecular baseline, the authors identify divergent phenotypic responses to neonatal DYRK1A reduction between males and females, with implications for how preclinical DS studies are designed and reported.

Sex as a biological variable in neurodevelopmental research has received increasing attention following requirements from funding bodies including the US National Institutes of Health to include both sexes in preclinical studies. This preprint contributes to the emerging picture that sex-disaggregated analysis reveals important mechanistic differences that aggregate analyses can obscure. This work is a preprint and has not yet completed peer review.