Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/ DiGeorge syndrome region

Puech, Anne; Saint-Jore, Bruno; Merscher, Sandra; Russell, Robert G.; Cherif, Dorra; Sirotkin, Howard I.; Xu, Hui; Factor, Stephen M.; Kucherlapati, Raju; Skoultchi, Arthur I.

doi:10.1073/pnas.97.18.10090

Cited by 56 publications

(34 citation statements)

References 37 publications

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“…This might be explained by differences in the genetic background of the mouse strains used (Threadgill et al, 1997). In studies that aimed to generate mouse models of DiGeorge Syndrome, 150-550 kb deletions of chromosome 16 including Tssk1 and Tssk2 were found to be lethal in a homozygous situation, but were transmitted by the heterozygous animals (Kimber et al, 1999;Puech et al, 2000). This is in agreement with our findings on transmission of the targeted Tssk1/2 allele.…”

Section: Discussionsupporting

confidence: 82%

Functional transformation of the chromatoid body in mouse spermatids requires testis-specific serine/threonine kinases

Shang

Baarends

Hoogerbrugge

et al. 2010

Journal of Cell Science

116

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SummaryThe cytoplasmic chromatoid body (CB) organizes mRNA metabolism and small regulatory RNA pathways, in relation to haploid gene expression, in mammalian round spermatids. However, little is known about functions and fate of the CB at later steps of spermatogenesis, when elongating spermatids undergo chromatin compaction and transcriptional silencing. In mouse elongating spermatids, we detected accumulation of the testis-specific serine/threonine kinases TSSK1 and TSSK2, and the substrate TSKS, in a ring-shaped structure around the base of the flagellum and in a cytoplasmic satellite, both corresponding to structures described to originate from the CB. At later steps of spermatid differentiation, the ring is found at the caudal end of the newly formed mitochondrial sheath. Targeted deletion of the tandemly arranged genes Tssk1 and Tssk2 in mouse resulted in male infertility, with loss of the CB-derived ring structure, and with elongating spermatids possessing a collapsed mitochondrial sheath. These results reveal TSSK1-and TSSK2-dependent functions of a transformed CB in post-meiotic cytodifferentiation of spermatids.

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Section: Discussionsupporting

confidence: 82%

Functional transformation of the chromatoid body in mouse spermatids requires testis-specific serine/threonine kinases

Shang

Baarends

Hoogerbrugge

et al. 2010

Journal of Cell Science

116

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“…This association, known as velocardiofacial (VCFS) or Shprintzen syndrome (33,34), most often (Ϸ90%) results from heterozygous microdeletions on the long arm of chromosome 22 (22q11.2del) (35)(36)(37). Several groups have recently engineered chromosomal deletions in the murine region homologous to the 22q11.2 human region (38)(39)(40). Their work led to the conclusion that several genes may be involved in the pathogenesis of the 22q11.2del DGS͞VCFS abnormalities, among which Tbx1 (24,25,40) and Crko1 (41) may be two critical determinants.…”

Section: Discussionmentioning

confidence: 99%

Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice

Vermot

Niederreither

Garnier

et al. 2003

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

146

115

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Retinoic acid (RA), the active derivative of vitamin A, is involved in various developmental and homeostatic processes. To define whether certain developmental events are particularly sensitive to a decrease in embryonic RA levels, we generated mice bearing a hypomorphic allele of the RA-synthesizing enzyme Raldh2. The resulting mutant mice, which die perinatally, exhibit the features of the human DiGeorge syndrome (DGS) with heart outflow tract septation defects and anomalies of the aortic arch-derived head and neck arteries, laryngeal-tracheal cartilage defects, and thymus͞parathyroid aplasia or hypoplasia. Analysis of Raldh2 hypomorph embryos reveal selective defects of the posterior (third to sixth) branchial arches, including absence or hypoplasia of the corresponding aortic arches and pharyngeal pouches, and local down-regulation of RA-target genes. Thus, a decreased level of embryonic RA (through genetic and͞or nutritional causes) could represent a major modifier of the expressivity of human 22q11del-associated DiGeorge͞velocardiofacial syndromes and, if severe enough, could on its own lead to the clinical features of the DiGeorge syndrome.

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“…Whether that also accounts for UFD1L and HIRA needs further investigation. A repressor function for DGCR6 is supported by the mouse models in which parts of chromosome 16, including Dgcr6, are deleted (18,52). These mice do not show cardiovascular anomalies.…”

mentioning

confidence: 90%

A Chicken Model for DGCR6 as a Modifier Gene in the DiGeorge Critical Region

et al. 2004

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DGCR6 is the most centromeric gene in the human DiGeorge critical region and is the only gene in the region with a second functional copy on a repeat localized more distally on chromosome 22. We isolated the chicken ortholog of DGCR6 and showed an embryonic expression pattern that is initially broad but becomes gradually restricted to neural crest cell derivatives of the cardiovasculature. Retrovirus based gene transduction was used to deliver sense and antisense messages to premigrating neural crest cells in vivo. Embryos in which DGCR6 expression was attenuated revealed cardiovascular anomalies reminiscent of those found in DiGeorge syndrome. Moreover, the expression profiles of three other genes from the DiGeorge critical region, TBX-1, UFD1L, and HIRA, were shown to be altered in this model. TBX-1 and UFD1L levels were increased, whereas HIRA was decreased in the hearts and pharyngeal arches of embryos treated with antisense or partial sense constructs, but not with sense constructs for DGCR6. The expression changes were transient and followed the normal DGCR6 expression profile. These data show that neural crest cells might have a role in the distribution of modulator signals to the heart and pharyngeal arches. Moreover, it shows a repressor function for DGCR6 on the expression of TBX-1 and UFD1L. For the first time, DiGeorge syndrome is shown to be a contiguous gene syndrome in which not only several genes from the critical region, but also different cell types within the embryo, interact in the development of the phenotype. Congenital anomalies can provide important clues for the impact of specific processes in embryonic development. With respect to the chromosome 22 deletion syndrome or DGS (OMIM 188400), a patient's phenotype is clearly related to disturbance of migration or differentiation of neural crest. This might also be evoked by an inadequate interaction with surrounding cells like the endo-and mesoderm in the pharyngeal arches. In DGS patients, cardiovascular anomalies often coincide with thymic, thyroid, and parathyroid defects (1). All these areas are populated by cephalic and cardiac NCC that delaminate from the dorsal neural tube during neurulation and enter the mesodermal compartment of the embryo (2-5). The chicken NCC ablation model (6) shows that these neural crest areas are preferentially disturbed in DGS. In this respect, it is remarkable that, of the cardiovasculature in DGS patients, primarily the cardiac outflow tract and the fourth pharyngeal arch arteries are affected, although all arch arteries as well as outflow and inflow tracts of the heart are invaded by NCC (5, 7). The DGS phenotype in general presents with IAA-B, PTA, VSD, and tetralogy of Fallot (8,9).Although the affected chromosomal region has been known for over a decade, pinpointing the gene(s) involved in DGS is difficult. Genomic analysis of patients revealed a hemizygously typical deleted region of 1.5-to 3.0-Mb on chromosome 22q1.1 carrying over 30 genes. This region appears highly unstable due to the presence of A...

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Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/ DiGeorge syndrome region

Cited by 56 publications

References 37 publications

Functional transformation of the chromatoid body in mouse spermatids requires testis-specific serine/threonine kinases

Functional transformation of the chromatoid body in mouse spermatids requires testis-specific serine/threonine kinases

Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice

A Chicken Model for DGCR6 as a Modifier Gene in the DiGeorge Critical Region

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