Department of Human and General Physiology, University of Bologna, Bologna, Italy.
Lab Invest. 2012 Nov;92(11):1648-60. doi: 10.1038/labinvest.2012.117. Epub 2012 Aug 13.
Down syndrome (DS) is a genetic pathology due to the triplication of human chromosome 21. In addition to mental retardation, individuals with DS exhibit a large range of variable traits, including co-occurring congenital malformations. It is now clear that neurogenesis impairment underlies the typically reduced brain size and, hence, mental retardation in individuals with DS. The small body size and the constellation of congenital malformations in children with DS suggest that proliferation defects may involve peripheral tissues, in addition to the brain. The goal of the current study was to establish whether a generalized impairment of cell proliferation is a key feature of the trisomic condition. We used the Ts65Dn mouse, a widely used DS model, and examined proliferation in tissues with different embryological origin by 5-bromo-2-deoxyuridine immunohistochemistry. We found that 2-day-old (P2) Ts65Dn mice had notably fewer proliferating cells in the heart and liver, and in all proliferating niches of the skin and intestine. A reduced proliferation rate was still present in the intestine at P15. In all tissues, Ts65Dn mice had a similar number of apoptotic cells as euploid mice, indicating no unbalance in cell death. In the skin, liver and intestine of trisomic mice, we found a higher expression of patched1 (Ptch1), a receptor that represses the mitogenic sonic hedgehog (Shh) pathway. This suggests that Ptch1-dependent inhibition of Shh signaling may underlie proliferation impairment in trisomic peripheral tissues. In agreement with the widespread reduction in proliferation, neonate trisomic mice had a reduced body weight and this defect was still present at 30 days of age. Our findings show that, in all examined peripheral tissues, Ts65Dn mice exhibit a notable reduction in proliferation rate, suggesting that proliferation impairment may be a generalized defect of trisomic precursor cells.
唐氏综合征（DS）是一种由于人类 21 号染色体三体而引起的遗传病理学。除了智力障碍，DS 患者还表现出广泛的可变性特征，包括同时发生的先天性畸形。现在很清楚，神经发生障碍是 DS 患者大脑体积通常减小的原因，因此也是智力障碍的原因。DS 患儿的体型较小和先天性畸形的组合表明，增殖缺陷可能不仅涉及大脑，还涉及外周组织。本研究的目的是确定细胞增殖的普遍受损是否是三体条件的一个关键特征。我们使用了 Ts65Dn 小鼠，这是一种广泛使用的 DS 模型，并通过 5-溴-2-脱氧尿苷免疫组织化学法检查了不同胚胎起源的组织中的增殖情况。我们发现，2 天大（P2）的 Ts65Dn 小鼠的心脏和肝脏以及皮肤和肠道的所有增殖部位中的增殖细胞明显减少。在 P15 时，肠道中的增殖率仍然较低。在所有组织中，Ts65Dn 小鼠的凋亡细胞数量与正常二倍体小鼠相似，表明细胞死亡没有失衡。在三体小鼠的皮肤、肝脏和肠道中，我们发现 patched1（Ptch1）的表达增加，Ptch1 是一种抑制有丝分裂 sonic hedgehog（Shh）途径的受体。这表明 Ptch1 依赖性的 Shh 信号抑制可能是三体周围组织增殖受损的基础。与广泛的增殖减少一致，新生三体小鼠的体重减轻，这种缺陷在 30 天时仍然存在。我们的研究结果表明，在所有检查的外周组织中，Ts65Dn 小鼠的增殖率明显降低，这表明增殖受损可能是三体前体细胞的普遍缺陷。
