The establishment of the cardiovascular system represents an early, critical event essential for normal embryonic development, and defects in cardiovascular development are a frequent cause of both in utero and neonatal demise. Congenital cardio-vascular malformations, the most frequent birth defect, can occur as isolated events, but are frequently presented clinically within the context of a constellation of defects that involve multiple organs and that define a specific syndrome. In addition, defects can be a primary effect of gene mutations or result from secondary effects of altered cardiac physiology. Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the heart, liver, eye, skeleton and kidney. Congenital heart defects, the majority of which affect the right-sided or pulmonary circulation, contribute significantly to mortality in AGS patients. Recently, mutations in Jagged1 ( JAG1 ), a conserved gene of the Notch intercellular signaling pathway, have been found to cause AGS. In order to begin to delineate the role of JAG1 in normal heart development we have studied the expression pattern of JAG1 in both the murine and human embryonic heart and vascular system. Here, we demonstrate that JAG1 is expressed in the developing heart and multiple associated vascular structures in a pattern that correlates with the congenital cardiovascular defects observed in AGS. These data are consistent with an important role for JAG1 and Notch signaling in early mammalian cardiac development.
A Robertsonian translocation results in a metacentric chromosome produced by the fusion of two acrocentric chromosomes. Rb heterozygous mice frequently generate aneuploid gametes and embryos, providing a good model for studying meiotic nondisjunction. We intercrossed mice heterozygous for a (7.18) Robertsonian translocation and performed molecular genotyping of 1812 embryos from 364 litters with known parental origin, strain, and age. Nondisjunction events were scored and factors influencing the frequency of nondisjunction involving chromosomes 7 and 18 were examined. We concluded the following: The frequency of nondisjunction among 1784 embryos (3568 meioses) was 15.9%.Nondisjunction events were distributed nonrandomly among progeny. This was inferred from the distribution of the frequency of trisomics and uniparental disomics (UPDs) among all litters.There was no evidence to show an effect of maternal or paternal age on the frequency of nondisjunction.Strain background did not play an appreciable role in nondisjunction frequency.The frequency of nondisjunction for chromosome 18 was significantly higher than that for chromosome 7 in males.The frequency of nondisjunction for chromosome 7 was significantly higher in females than in males. These results show that molecular genotyping provides a valuable tool for understanding factors influencing meiotic nondisjunction in mammals.
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