Biomedical subjects

Jean Maurice Delabar

Publications and source records attributed to Jean Maurice Delabar.

4 recordsLinked to original sources

PubMed2006

Developmental defects in trisomy 21 and mouse models.

Aneuploidies have diverse phenotypic consequences, ranging from mental retardation and developmental abnormalities to susceptibility to common phenotypes and various neoplasms. This review focuses on the developmental defects of murine models of a prototype human aneuploidy: trisomy 21 (Down syndrome, DS, T21). Murine models are clearly the best tool for dissecting the phenotypic consequences of imbalances that affect single genes or chromosome segments. Embryos can be studied freely in mice, making murine models particularly useful for the characterization of developmental abnormalities. This review describes the main phenotypic alterations occurring during the development of patients with T21 and the developmental abnormalities observed in mouse models, and investigates phenotypes common to both species.

Aneuploidy↗

PubMed2006

Paraoxonase-1 expression is up-regulated in Down syndrome fetal liver.

Patients with Down syndrome appear to be protected from the development of atherosclerosis. On the contrary, hyperhomocysteinemia is associated with an increased risk for atherosclerosis. As hyperhomocysteinemia due to cystathionine beta synthase deficiency is associated with a decreased expression of paraoxonase-1, a major anti-atherosclerotic component secreted by the liver, we aimed to analyze the expression of paraoxonase-1 and cystathionine beta synthase in Down syndrome fetal liver by quantitative real-time reverse transcriptase-polymerase chain reaction. Paraoxonase-1 was up-regulated in Down syndrome fetal liver, while cystathionine beta synthase gene expression in Down syndrome fetuses was similar to the gene level in control fetuses. Moreover, there was no evidence for an association between paraoxonase-1 genotypes influencing paraoxonase-1 gene expression and Down syndrome. Since most serum paraoxonase-1 is synthesized in the liver, an increase of hepatic paraoxonase-1 expression might be one of the factors which could explain the low incidence of atherosclerotic vascular disease in Down syndrome.

Aryldialkylphosphatase↗

PubMed2004

Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration.

Down syndrome is the most frequent genetic cause of mental retardation, having an incidence of 1 in 700 live births. In the present study we used a transgenic mouse in vivo library consisting of 4 yeast artificial chromosome (YAC) transgenic mouse lines, each bearing a different fragment of the Down syndrome critical region 1 (DCR-1), implicated in brain abnormalities characterizing this pathology. The 152F7 fragment, in addition to genes also located on the other DCR-1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing 152F7 mice but not the other lines display learning impairment and hyperactivity during development. Additionally, 152F7 mice display increased brain weight and neuronal size. At a biochemical level we found DYRK1A overexpression associated with a development-dependent increase in phosphorylation of the transcription factor FKHR and with high levels of cyclin B1, suggesting for the first time in vivo a correlation between DYRK1A overexpression and cell cycle protein alteration. In addition, we found an altered phosphorylation of transcription factors of CREB family. Our findings support a role of DYRK1A overexpression in the neuronal abnormalities seen in Down syndrome and suggest that this pathology is linked to altered levels of proteins involved in the regulation of cell cycle.

Animals↗

PubMed2003

The differentially expressed C21orf5 gene in the medial temporal-lobe system could play a role in mental retardation in Down syndrome and transgenic mice.

Mental retardation represents the more invalidating pathological aspect of Down syndrome, DS, and has a hard impact in public health. Modifications in DS brain, concerning abnormal size, neuronal differentiation, and cell density, cause changes in the neurophysiology and behavior of DS patients, and could be determined by dosage imbalance of genes localized in the DS critical region, DCR. Among these genes, C21orf5 showed high homology with Caenorhabditis elegans Pad1 involved in cellular differentiation and patterning. To shed light on C21orf5 role in DS, we performed molecular characterization of human and mouse orthologs, their spatio-temporal expression during development and in adult, and overexpression in DS and transgenic mice. C21orf5 was widely expressed early in embryogenesis in the nervous system. Later, its expression became differential and increased in mesencephalon and rhomboencephalon. This developmental expression profile evolves selectively in adult brain with higher signals in hippocampus, cerebellum, perirhinal, and entorhinal cortex, compared to the other cortical regions. Cellular specificity was detected in hippocampus with higher C21orf5 mRNA level in CA3 cells. Our findings appoint C21orf5 as candidate gene for mental retardation: Its overexpression in DS cells may contribute to gene imbalance in DS.Its specific expression in normal and its mirroring pattern in transgenic mice correspond to abnormal regions in DS patients and to neurological phenotype of transgenic mice. Altered cortical lamination in transgenic mice and the Pad1 ortholog function suggest a potential role of C21orf5 in cell differentiation. Its patterned differential expression in the medial temporal-lobe system, including hippocampal formation and perirhinal cortex involved in memory storage, and learning and memory defects in the transgenic mice suggest a specialized role for C21orf5 in cognitive processes. These evidences suggest that C21orf5 is an attractive candidate gene contributing to neurological alterations responsible for mental retardation in DS patients.

Animals↗