Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with down syndrome and in Ts65Dn mice
Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with down syndrome and in Ts65Dn mice
复制标题
DOI：
10.1002/hipo.20308
复制
发表时间：
2007-01-01
期刊：
影响因子：
3.5
通讯作者：
Ciani, Elisabetta
中科院分区：
文献类型：
--
作者：
Contestabile, Andrea;Fila, Tatiana;Ciani, Elisabetta
唐氏综合症（DS）是导致智力低下的主要遗传原因，其特征是皮质神经元数量和大脑尺寸减少。这些缺陷从生命早期阶段开始出现，表明发育性神经发生的改变是其主要决定因素。我们研究的目的是获得 DS 胎儿和 Ts65Dn 小鼠（DS 动物模型）海马齿状回 (DG) 神经发生受损的比较证据。使用 Ki-67（细胞周期 S + G(2) + M 期细胞标记物）和细胞周期蛋白 A（S 期细胞标记物）免疫组织化学评估人类胎儿细胞增殖。我们发现，与对照组相比，DS 胎儿的 DC 中增殖细胞的数量显着减少。在侧脑室的生发基质中观察到类似的减少。在这两种结构中，与对照组相比，DS 胎儿的细胞周期蛋白 A 和 Ki-67 阳性细胞之间的比例降低，表明它们处于 S 期的循环细胞数量减少。在注射溴脱氧尿苷 (BrdU) 2 小时后评估，在 P2 Ts65Dn 小鼠的 DG 中，细胞增殖显着减少，与 DS 胎儿类似。 28 天后，Ts65Dn 小鼠的 BrdU 阳性细胞仍少于对照组。对存活细胞的表型分析表明，Ts65Dn 小鼠具有星形胶质细胞表型的细胞百分比数量大于对照组。使用磷酸组蛋白 H3 免疫组织化学，我们发现 DS 胎儿和 P2 Ts65Dn 小鼠在 G2 期的增殖细胞数量较多，而在细胞周期的 M 期细胞数量较少。结果为 DS 胎儿脑海马 DG 的增殖损伤提供了新的证据，与 P2 小鼠模型的情况相当，并表明细胞周期的改变可能是增殖能力降低的关键决定因素。 (c) 2007 年 Wiley-Liss, Inc.
Down syndrome (DS), the leading genetic cause of mental retardation, is characterized by reduced number of cortical neurons and brain size. The occurrence of these defects starting from early life stages points at altered developmental neurogenesis as their major determinant. The goal of our study was to obtain comparative evidence for impaired neurogenesis in the hippocampal dentate gyrus (DG) of DS fetuses and Ts65Dn mice, an animal model for DS. Cell proliferation in human fetuses was evaluated with Ki-67 (a marker of cells in S + G(2) + M phases of cell cycle) and cyclin A (a marker of cells in S phase) immunohistochemistry. We found that in the DC of DS fetuses the number of proliferating cells was notably reduced when compared with controls. A similar reduction was observed in the germinal matrix of the lateral ventricle. in both structures, DS fetuses showed a reduced ratio between cyclin A- and Ki-67-positive cells when compared with controls, indicating that they had a reduced number of cycling cells in S phase. In the DG of P2 Ts65Dn mice cell proliferation, assessed 2 h after an injection of bromodeoxyuridine (BrdU), was notably reduced, similarly to DS fetuses. After 28 days, Ts65Dn mice had still less BrdU-positive cells than controls. Phenotypic analysis of the surviving cells showed that Ts65Dn mice had a percent number of cells with astrocytic phenotype larger than controls. Using phospho-histone H3 immunohistochemistry we found that both DS fetuses and P2 Ts65Dn mice had a higher number of proliferating cells in G2 and a smaller number of cells in M phase of cell cycle. Results provide novel evidence for proliferation impairment in the hippocampal DG of the DS fetal brain, comparable to that of the P2 mouse model, and suggest that cell cycle alterations may be critical determinants of the reduced proliferation potency. (c) 2007 Wiley-Liss, Inc.