Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression
Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression
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DOI：
10.1038/labinvest.2012.117
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发表时间：
2012-11-01
影响因子：
5
通讯作者：
Bartesaghi, Renata
中科院分区：
文献类型：
--
作者：
Fuchs, Claudia;Ciani, Elisabetta;Bartesaghi, Renata
唐氏综合征(DS)是一种由人类21号染色体三倍体引起的遗传病理。除了智力迟缓，DS患者还表现出一系列不同的特征，包括共同发生的先天性畸形。现在很清楚的是，神经发生障碍是DS患者典型的脑体积缩小和智力低下的基础。DS儿童的小身体和先天畸形星座表明，除了大脑外，增殖性缺陷可能还涉及到周围组织。目前这项研究的目的是确定细胞增殖的全身性损害是否是三体疾病的关键特征。我们使用了广泛使用的DS模型Ts65Dn小鼠，并用5-溴-2-脱氧尿苷免疫组织化学方法检测了不同胚胎学来源的组织的增殖情况。我们发现，出生2天(P2)的Ts65Dn小鼠的心脏和肝脏以及皮肤和肠道的所有增殖壁龛中的增殖细胞明显较少。在P15时，肠道的增殖率仍较低。在所有组织中，Ts65Dn小鼠的凋亡细胞数量与整倍体小鼠相似，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(Ptchl)的高表达，Ptchl是一种抑制有丝分裂的sonic hedgehog(Shh)途径的受体。这表明ptch1依赖的Shh信号抑制可能是导致三体外周组织增殖损伤的原因。与广泛的增殖减少一致的是，新生的三体小鼠体重减轻，这种缺陷在30天大时仍然存在。我们的研究结果表明，在所有被检测的外周组织中，Ts65Dn小鼠的增殖率显著降低，表明增殖障碍可能是三体前体细胞的一种全身性缺陷。实验室调查(2012年)92,1648年至1660年；doi：10.1038/Labinvest.2012.117；2012年8月13日在线发布
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 (Ptchl), 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. Laboratory Investigation (2012) 92, 1648-1660; doi:10.1038/labinvest.2012.117; published online 13 August 2012