Academic journal article Genetics

Trisomic and Allelic Differences Influence Phenotypic Variability during Development of Down Syndrome Mice

Academic journal article Genetics

Trisomic and Allelic Differences Influence Phenotypic Variability during Development of Down Syndrome Mice

Article excerpt

ABSTRACT Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the "Down syndrome critical region" or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS.

DOWN syndrome (DS) is caused by three copies of all or part of human chromosome 21 (Hsa21) and occurs in 1 of 700-800 live births (Christianson et al. 2006). Individuals with DS display subsets of phenotypes with a spectrum of severities including cognitive impairment, facial dysmorphology, congenital heart defects, and behavioral anomalies (Richtsmeier et al. 2000; Epstein 2001; Van Cleve et al. 2006; Van Cleve and Cohen 2006). The precise genetic and molecular mechanisms causing specific traits associated with Trisomy 21 (Ts21) are not well defined. Early genotype- phenotype analyses based on individuals with partial Ts21 were used to define a "Down syndrome critical or chromosomal region" (DSCR), and trisomy of the DSCR was thought to be responsible for most of the major clinical features of DS (Korenberg et al. 1990; Delabar et al. 1993). Experiments in mice with segmental trisomy for the DSCR disproved the original DSCR hypothesis by demonstrating that genes in the DSCR were not sufficient to cause the craniofacial features associated with DS (Olson et al. 2004a). Advanced analyses of individuals with segmental Ts21 have presented evidence against a single critical region affecting all DS phenotypes and led to the hypothesis that three copies of a gene or genes on Hsa21 (not the entire DSCR or only the DSCR) may be an important factor for one or a few well-defined DS abnormalities (Korbel et al. 2009; Lyle et al. 2009).

The correlation between DS genotype and phenotype has been investigated using mouse models trisomic for Hsa21 homologs (Table 1) (Escorihuela et al. 1995; Siarey et al. 1997; Baxter et al. 2000; Olson et al. 2004a, 2007; Lorenzi and Reeves 2006; Aldridge et al. 2007; Belichenko et al. 2009). Ts65Dn mice, the most commonly used mouse model of DS, replicate many DS-like abnormalities, including a small mandible and other craniofacial phenotypes (Richtsmeier et al. 2000). The Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr) mouse model, trisomic for the 33 genes orthologous to those in the DSCR (and triplicated in Ts65Dn mice), was developed to test the DSCR hypothesis by examining craniofacial phenotypes in mice. Ts1Rhr mice exhibited a larger overall size and craniofacial alterations, including a larger and morphologically different mandible than observed in Ts65Dn mice and individuals with DS (Olson et al. …

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