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Sex-specific developmental phenotypes and their response to neonatal Dyrk1a reduction in the Ts65Dn Down syndrome
Alyssa Duerst1,2, Laura Hawley1,2, Linnea Johnson1
1Department of Biology, Indiana University Indianapolis, 723 W Michigan Street, SL306, Indianapolis, IN 46202, USA.
Insights
Down syndrome (DS) involves developmental delays linked to DYRK1A gene overexpression. Normalizing Dyrk1a copy number in DS model mice improved some physical and behavioral outcomes, offering insights for therapeutic interventions.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Down syndrome (DS) is characterized by cognitive, physical, and motor developmental delays.
- Overexpression of the Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) gene, located on chromosome 21, contributes to neurodevelopmental issues in DS.
- The Ts65Dn mouse model exhibits trisomy for approximately 100 human chromosome 21 orthologs, including Dyrk1a, with significant DYRK1A overexpression.
Purpose of the Study:
- To investigate if normalizing Dyrk1a copy number in Ts65Dn DS model mice before postnatal day 6 (P6) can ameliorate physical and behavioral deficits.
- To establish a baseline for evaluating the efficacy of future therapies targeting DYRK1A in DS.
Main Methods:
- Ts65Dn DS model pups were utilized, with Dyrk1a copy number normalized in a subset of mice (Ts,Dyrk1a+/+/Dox-Cre).
- Developmental assessments, including physical, motor, and behavioral tests, were conducted from postnatal days 3 to 21 (P3-P21).
- Sex-specific developmental outcomes were analyzed in comparison to euploid controls.
Main Results:
- Ts65Dn mice displayed sex-specific deficits in physical, motor, and behavioral development between P3-P21.
- Male Ts,Dyrk1a+/+/Dox-Cre mice showed enhanced emergence to running by P19.
- Both male and female Ts,Dyrk1a+/+/Dox-Cre mice exhibited reduced isolation-induced ultrasonic vocalizations during the second postnatal week.
Conclusions:
- Partial normalization of Dyrk1a copy number in Ts65Dn mice led to improvements in specific developmental phenotypes.
- The study highlights the complex interplay of genetic factors and developmental timing in DS phenotypes.
- Further research is needed to understand why not all abnormal phenotypes were improved, potentially due to gene/protein level dysregulation or the involvement of other trisomic genes.
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.
