Congenital heart disease in mice deficient for the DiGeorge syndrome region

Lindsay, Elizabeth A.; Botta, Annalisa; Jurecic, Vesna; Carattini-Rivera, Sandra; Cheah, Yin-Chai; Rosenblatt, Howard M.; Bradley, Allan; Baldini, Antonio

doi:10.1038/43900

Cited by 341 publications

(266 citation statements)

References 21 publications

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“…At embryonic day (E) 18.5, these animals displayed characteristic DGS/VCFS-like aortic arch defects, resulting from aplasia or hypoplasia of the fourth aortic arch artery earlier in development. Rescue of the phenotype was accomplished by genetic complementation with PACs or human BACs containing Tbx1 (Lindsay et al, 1999(Lindsay et al, , 2001Merscher et al, 2001). Null mutations of Tbx1 in the heterozygous state recapitulated the aortic arch anomalies seen in animals with large hemizygous chromosomal deletions.…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

Roberts¹,

Ivins²,

James³

et al. 2005

Developmental Dynamics

105

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Both Tbx1 and retinoic acid (RA) are key players in embryonic pharyngeal development; loss of Tbx1 produces DiGeorge syndrome-like phenotypes in mouse models as does disruption of retinoic acid homeostasis. We have demonstrated that perturbation of retinoic acid levels in the avian embryo produces altered Tbx1 expression. In vitamin A-deficient quails, which lack endogenous retinoic acid, Tbx1 expression patterns were disrupted early in development and expression was subsequently lost in all tissues. "Gain-of-function" experiments where RA-soaked beads were grafted into the pharyngeal region produced localized down-regulation of Tbx1 expression. In these embryos, analysis of Shh and Foxa2, upstream control factors for Tbx1, suggested that the effect of RA was independent of this regulatory pathway. Real-time polymerase chain reaction analysis of retinoic acid-treated P19 cells showed a dosedependent repression of Tbx1 by retinoic acid. Repression of Tbx1 transcript levels was first evident after 8 -12 hr in culture in the presence of retinoic acid, and to achieve the highest levels of repression, de novo protein synthesis was required. Developmental Dynamics 232:928 -938, 2005.

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Section: Introductionmentioning

confidence: 99%

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

Roberts¹,

Ivins²,

James³

et al. 2005

Developmental Dynamics

105

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“…We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21)(22)(23)(24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs.…”

mentioning

confidence: 99%

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Horev

Ellegood²,

Lerch³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

313

342

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Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.Home-cage | stereotypic behavior | structural variation | brain MRI A ccumulating evidence suggests the importance of copy number variations (CNVs) in the etiology of neuropsychiatric disorders, including autism (1), schizophrenia (2-4), developmental delay (5), and other complex traits (6). The 16p11.2 region is particularly intriguing. Whereas deletion of 16p11.2 has been associated with autism (7-9), duplication of 16p11.2 has been associated with autism (9, 10) as well as schizophrenia (11). 16p11.2 CNVs have also been reported in patients with developmental delay, mental retardation, repetitive behaviors (12-16), and a highly penetrant form of obesity (17). A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16). These studies reveal the variability of symptoms in patients carrying the same 16p11.2 CNV, an extreme example being a family with three affected members with symptoms so heterogeneous that they were barely overlapping (18).Mouse models allow direct assessment of CNVs while reducing variability caused by genetic and environmental factors. We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21-24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27)). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs. Because of the evidence for clinical heterogeneity, we screened these models for multiple changes in brain anatomy and behavior by usin...

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“…After several attempts to find the gene responsible for this syndrome (Lindsay et al, 1999;Gong et al, 2001), and having a clear clue that Tbx1 was responsible for part of the phenotypes in mice, human patients having the clinical phenotype of DGS, but not a distinguishable deletion were found to harbor mutations in TBX1 (Yagi et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…del (17) (Jacks et al, 1994) (Brannan et al, 1994) Nf1 tissue specific inactivation (Gitler et al, 2003) Holoprosencephaly 4 (HPE4) del (18) Single and double targeted mutagenesis (Jag1 null and Notch2 hypomorph); (Xue et al, 1999;McCright et al, 2002) Holoprosencephaly 1 (HPE1) del (21) (Lindsay et al, 1999;Merscher et al, 2001); nested deletions; Tbx1 and Crk1 targeted mutagenesis (Jerome et al, 2001;Guris et al, 2001); transgenesis Merscher et al, 2001;Funke et al, 2001); Raldh2 hypomorph (Vermot, 2003) Adrenal hypoplasia congenita (AHC) and reciprocal Dosage-Sensitive Sex Reversion (DSS) (Yu et al, 1998); Dax1 transgenesis (Swain et al, 1998) Pelizaeus-Merzbacher (PMD) del(X)(q22q22) and dup(X)(q22q22) 312080 PLP Jimpy mouse (Dautigny et al, 1986;Nave et al, 1986;Sidman, 1964); PLP/DMD20 targeted mutagenesis (Klugmann et al, 1997); PLP transgenesis (Readhead et al, 1994;Inoue et al, 1996) Microphtalmia with Linear Skin Defects Syndrome (MLS) del(X)(p22.31q22.31) 309801 HSSC for male lethality? Chromosome engineering and transgenesis (Prakash et al, 2002) Duchenne Muscular Dystrophy (DMD) del(X)(p21.2p21.2) 310200 DMD Mdx mouse model (Sicinski et al, 1989); inducible transgenesis (Ahmad et al, 2000); transgenesis (Cox et al, 1993;Phelps et al, 1995;Rafael et al, 1996;Wells et al, 1995) Hyperglycerolemia (GKD) del(X)(p21p21) 307030 GK Gyk targeted mutagenesis (Huq et al, 1997) usually occurs in most patients because of the molecular mechanism that results in fixed breakpoints reflecting genome architecture.…”

Section: Pmp22mentioning

confidence: 99%

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Animal models for human contiguous gene syndromes and other genomic disorders

2004

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Genomic disorders refer to a group of syndromes caused by DNA rearrangements, such as deletions and duplications, which result in an alteration of normal gene dosage. The chromosomal rearrangements are usually relatively small and often difficult to detect cytogenetically. In a subset of such conditions the rearrangements comprise multiple unrelated contiguous genes that are physically linked and thus have been referred to as contiguous gene syndromes (CGS). In general, each syndrome presents a complex clinical phenotype that has been attributed generally to dosage sensitive gene(s) present in the responsible chromosomal interval. A common mechanism for CGS resulting from interstitial deletion/duplication has recently been elucidated. The DNA rearrangements result from nonallelic homologous recombination (NAHR) utilizing flanking low-copy repeats (LCRs) as recombination substrates. The resulting rearrangements often involve the same genomic region, a common deletion or duplication, making it difficult to assign a specific phenotype or endophenotype to a single responsible gene. The human and mouse genome sequencing projects, in conjunction with the ability to engineer mouse chromosome rearrangements, have enabled the production of mouse models for CGS and genomic disorders. In this review we present an overview of different techniques utilized to generate mouse models for selected genomic disorders. These models foment novel insights into the specific genes that convey the phenotype by dosage and/or position effects and provide opportunities to explore therapeutic options.

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Congenital heart disease in mice deficient for the DiGeorge syndrome region

Cited by 341 publications

References 21 publications

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Animal models for human contiguous gene syndromes and other genomic disorders

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