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bioRxiv · 10.64898/2026.07.15.738703

Sex-specific developmental phenotypes and their response to neonatal Dyrk1a reduction in the Ts65Dn Down syndrome mouse model

Duerst, A.·Hawley, L.·Johnson, L.·Obeid, Z.·Snellenberger, L.·Folz, A.·Goodlett, C. R. R.·Roper, R.
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Abstract

Children with Down syndrome (DS) experience delays in cognitive, physical, and motor development. Overexpression of Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), a gene on human chromosome 21 (Hsa21) and triplicated in individuals with Trisomy 21, contributes to neurodevelopmental delays associated with DS, and is a candidate for therapies to improve neurodevelopmental phenotypes. Male and female Ts65Dn DS model pups are trisomic for [~]100 Hsa21 orthologs including Dyrk1a, and both sexes show significant DYRK1A overexpression on postnatal day 6 (P6) in the hippocampus, cerebral cortex, and cerebellum. This study tested the hypothesis that normalization of Dyrk1a copy number in Ts65Dn pups prior to P6 would diminish physical and behavioral developmental outcomes in Ts65Dn mice, thus providing a standard of comparison for success of interventions targeting Dyrk1a. At P3-P21, Ts65Dn compared to euploid pups showed sex-specific deficits in physical, motor, and behavioral development. Male Ts,Dyrk1a+/+/Dox-Cre mice showed improved emergence to running on P19, and both sexes of Ts,Dyrk1a+/+/Dox-Cre mice exhibited reduced isolation-induced ultrasonic vocalizations during the second postnatal week. Dyrk1a normalization in Ts65Dn pups did not improve all abnormal phenotypes, perhaps because of developmental dysregulation between Dyrk1a RNA and DYRK1A protein levels, involvement of other trisomic genes, or improvements in only adult mice.

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Duerst, A., Hawley, L., Johnson, L., Obeid, Z., Snellenberger, L., Folz, A., Goodlett, C. R. R., Roper, R.. 2026-07-17. Sex-specific developmental phenotypes and their response to neonatal Dyrk1a reduction in the Ts65Dn Down syndrome mouse model. https://doi.org/10.64898/2026.07.15.738703

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