Moyer, A. J. | Search bioRxiv

bioRxiv2022

A Mouse Model with Complete Penetrance for Atrioventricular Septal Defect/Complete AV Canal

Complete Atrioventricular Septal Defect/complete AV canal (AVSD/ cAVC) occurs via defective formation of the Dorsal Mesenchymal Protrusion (DMP) which grows from the interior dorsal wall of the fetal heart. The DMP is derived from cells of the second heart field (SHF). AVSD occurs in about 1/10,000 births in the general population, but is 2000 times more prevalent in individuals with Down syndrome (DS). The low penetrance of AVSD in the general population remains a fundamental challenge to investigation of the genetic and developmental basis for this condition. Analysis of the etiology of this condition in mouse models is limited by the fact that the developmental events producing the DMP begin around embryonic day 9 (E9) but AVSD cannot be diagnosed until E14, and no model has been described previously in which AVSD occurs in 100% of embryos. We describe a trisomic mouse DS model with conditional mutations in the SHH pathway that produces AVSD with 100% penetrance. This new mouse model can serve as an important tool to understand the mechanisms underlying AVSD pathogenesis.

developmental biology↗

bioRxiv2021

The first transchromosomic rat model with human chromosome 21 shows robust Down syndrome features

Progress in earlier detection and symptom management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available due to technical challenges. We developed the first transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein coding genes. RNA-Seq of neonatal forebrains demonstrates that TcHSA21rat not only expresses HSA21 genes but also has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, a prominent feature of DS that is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.

genetics↗