Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome

Abstract

Using Down syndrome as a model for complex trait analysis, we sought to identify loci from chromosome 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. We generated low-copy-number transgenic mice, containing four different yeast artificial chromosomes (YACs) that together cover approximately 2 megabases (Mb) of contiguous DNA from 21q22.2. We subjected independent lines derived from each of these YAC transgenes to a series of behavioural and learning assays. Two of the four YACs caused defects in learning and memory in the transgenic animals, while the other two YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region contains the human homologue of a Drosophila gene, minibrain, and strongly implicates it in learning defects associated with Down syndrome.

Increased Dosage of DYRK1A and Brain Volumetric Alterations in a YAC Model of Partial Trisomy 21

“…As DYRK1A is overexpressed in brain regions showing different levels of volume variation, the morphogenetic consequences of this overexpression may be modulated by an interaction between the product of this gene and various territory-restricted developmental pathways or interactor levels. Such changes in the volume of the central regions of the brain reveal alterations in developmental programming, which may also have induced changes in the patterns of innervation and connection between the various parts of the brain, with consequences for cognition (Smith et al, 1997;Branchi et al, 2004). Stereological studies on heterozygous mice with one copy of DYRK1A have shown that changes in the dosage of this gene induce an increase in pyramidal cell density, together with lower levels of dendritic arborization (Benavides-Piccione et al, 2005).…”

“…The two YAC strains have been described elsewhere (Smith et al, 1997;Branchi et al, 2004; YAC152F7 contains the genes PIGP, TTC3, DSCR9, DSCR3, DYRK1A, and YAC141G6 contains the genes DSCR6, PIGP, TTC3, DSCR9, DSCR3). Genotyping is described in the supplementary data section.…”

“…Smith et al (1997) constructed low copy number transgenic mice containing four different human yeast artificial chromosomes (YACs) encompassing approximately 2 Mb (i.e., 80%) of DCR-1 in total. This panel was used as an in vivo library for phenotype screening.…”

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

“…As mentioned above, evidence for the role of DYRK1A in various DS phenotypes is partially derived from studies performed in several segmental trisomic mouse models of DS that overexpress different sets of orthologous genes of human chromosome 21 (Hsa21), including Dyrk1A (Rueda et al, 2012;Bartesaghi et al, 2011) and in transgenic mice overexpressing DYRK1A in artificial bacterial or yeast chromosomes or carrying extra copies of the corresponding murine cDNA (De la Torre et al, 2014;Ahn et al, 2006;Altafaj et al, 2001;Smith et al, 1997).…”

Neurotrophin-4 is required for tolerance to morphine in the mouse

“…The following day the mice were challenged with 9 mg kg 21 morphine and again tested. Sensitization was assessed [6,15] by quantitating locomotor activity using the Cage Rack System (San Diego Instruments) [12,13]. This system uses a uniformly spaced 8 £ 4 photobeam grid to monitor activity in cages 47 (long) £ 26 (short) £ 15 cm (high).…”