The trisomy of Abcg1-U2af1 displayed impairment in working memory, in novel object recognition and overexpression of the conserved genes, except Abcg1 which was inactivated during VE-822 1232416-25-9 genetic engineering and U2af1, which is located outside the interval. All the genes from Abcg1-U2af1 genetic interval are trisomic in the Tc1 mouse model except the Ndufv3 gene which is rearranged. The corresponding monosomy Ms2Yah carries a deletion of the 12 conserved genes, plus the last exons of Abcg1, and showed fear conditioning and social recognition defects. To determine whether the region could play a role in several DS phenotypes observed in the Tc1 mouse model, Ms2Yah and Tc1 mouse models were examined for impairments in Open-Field, Morris water maze and rotarod. The present study highlights the contribution of the Abcg1-U2af1 genetic interval to DS-related features in Tc1 mouse models. We found that reducing the genetic dosage of this region in the Tc1 mouse models rescued subtle impairments in reversal learning, working memory and did so partially in the rotarod test, but had no impact on hyperactivity or spatial learning. Although all the genotypes finally learned where the platform was located in the probe test, the decrease in the performance of the Tc1 group could be associated with a lack of cognitive flexibility, since learning memory was not altered. This particular phenotype is observed in Down syndrome people and our results suggest that an increase in one or more genes of the Abcg1-U2af1 region contributes to decreased behavioral flexibility. Tc1 mice have severe deficits in motor skills in different motor coordination tasks such as rotarod, static rod and footprint tests. Rotarod performance analysis in our study confirmed the deficit in the locomotor activity of Tc1 mice, which occurred in the training days and in the test phase. After consecutive days of training, mice usually enhance their performance by staying on the rod longer each day. In our experiment, Tc1 and Tc1/Ms2Yah did not improve their performance in the learning phase. The learning mechanisms of locomotor function were altered, and decreasing the number of copies of the Abcg1-U2af1 region could not rescue them. During the test phase with different increasing rotarod speeds, Tc1 mice displayed strong impairment compared to controls. The Tc1/Ms2Yah showed better performance by staying longer and at higher speed on the rod than the Tc1 group. We exclude a strong contribution of the genetic background to this phenotype since the C3H fell earlier than the B6 in a similar protocol and the learning phase was not compensated. Thus, even if the Ms2Yah region is not implicated directly in motor learning, at least the over-expression of one or more genes located in the interval definitely modifies locomotor activity. During fertilization, oocytes resume their meiotic division upon penetration by sperm. Thereafter, the initial cleavage of the zygote early in embryogenesis proceeds without differentiation and growth of the zygote until successful implantation in the mother’s uterus occurs.