Increased male reproductive success in Ts65Dn “Down syndrome” mice

Abstract

The Ts65Dn mouse is trisomic for orthologs of about half the genes on Hsa21. A number of phenotypes in these trisomic mice parallel those in humans with trisomy 21 (Down syndrome), including cognitive deficits due to hippocampal malfunction that are sufficiently similar to human that “therapies” developed in Ts65Dn mice are making their way to human clinical trials. However, the impact of the model is limited by availability. Ts65Dn cannot be completely inbred and males are generally considered to be sterile. Females have few, small litters and they exhibit poor care of offspring, frequently abandoning entire litters. Here we report identification and selective breeding of rare fertile males from two working colonies of Ts65Dn mice. Trisomic offspring can be propagated by natural matings or by in vitro fertilization (IVF) to produce large cohorts of closely related siblings. The use of a robust euploid strain as recipients of fertilized embryos in IVF or as the female in natural matings greatly improves husbandry. Extra zygotes cultured to the blastocyst stage were used to create trisomic and euploid embryonic stem (ES) cells from littermates. We developed parameters for cryopreserving sperm from Ts65Dn males and used it to produce trisomic offspring by IVF. Use of cryopreserved sperm provides additional flexibility in the choice of oocyte donors from different genetic backgrounds, facilitating rapid production of complex crosses. This approach greatly increases the power of this important trisomic model to interrogate modifying effects of trisomic or disomic genes that contribute to trisomic phenotypes.

Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice

“…Ts65Dn mice are difficult to breed compared to Dp(16)1Yey mice, in part, because male Ts65Dn mice are typically sterile [Davisson et al, 2007; Moore et al, 2010]. Of note, human males with DS are usually sterile, but male Dp(16)1Yey mice are fertile.…”

Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF

“…Here, we tested the therapeutic effects of BACE1 inhibition in a trisomic mouse line (Ts2) by deleting one BACE1 allele (Ts2.BACE1 +/- ) to lower BACE1 expression while avoiding undesirable effects of complete BACE1 deletion on synaptic function, neuroplasticity, and behavior (Kobayashi, et al, 2008; Laird, et al, 2005). We used the Ts[Rb(12.17 16 )]2Cje (Ts2) DS model (Villar, et al, 2005) because the commonly used Ts65Dn mouse model is challenging to breed (Moore, et al, 2010). By contrast, the Ts2 mouse, which expresses the same complement of trisomic genes as Ts65Dn and displays the same overt DS phenotype, yields male mice that are fertile and female mice that have higher trisomy transmission rates, resulting in a ∼3-fold higher viable offspring compared to Ts65Dn mice.…”

Aneuploidy and Skeletal Health

“…In fact, the low bone mass phenotype was observed in a murine Down syndrome model (Ts65Dn) 8,35 , and was treatable with intermittent parathyroid hormone 8 . The decreased bone turnover in Down syndrome is an entirely unexpected result, given the hypogonadism and infertility apparent in both animals and humans with the disorder 52,53 . Although hypogonadism is a consistent finding in men with Down syndrome, 10,28,54 the pathophysiology of the infertility in men with Down syndrome remains unclear.…”