Dutka Tara, Hallberg Dorothy, Reeves Roger H
Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mech Dev. 2015 Feb;135:68-80. doi: 10.1016/j.mod.2014.11.004. Epub 2014 Dec 12.
Down Syndrome (DS) is a highly complex developmental genetic disorder caused by trisomy for human chromosome 21 (Hsa21). All individuals with DS exhibit some degree of brain structural changes and cognitive impairment; mouse models such as Ts65Dn have been instrumental in understanding the underlying mechanisms. Several phenotypes of DS might arise from a reduced response of trisomic cells to the Sonic Hedgehog (SHH) growth factor. If all trisomic cells show a similar reduced response to SHH, then up-regulation of the pathway in trisomic cells might ameliorate multiple DS phenotypes. We crossed Ptch1tm1Mps/+ mice, in which the canonical SHH pathway is expected to be up-regulated in every SHH-responsive cell due to the loss of function of one allele of the pathway suppressor, Ptch1, to the Ts65Dn DS model and assessed the progeny for possible rescue of multiple DS-related phenotypes. Down-regulation of Ptch produced several previously unreported effects on development by itself, complicating interpretation of some phenotypes, and a number of structural or behavioral effects of trisomy were not compensated by SHH signaling. However, a deficit in a nest-building task was partially restored in Ts;Ptch+/- mice, as were the structural anomalies of the cerebellum seen in Ts65Dn mice. These results extend the body of evidence indicating that reduced response to SHH in trisomic cells and tissues contributes to various aspects of the trisomic phenotype.
唐氏综合征（DS）是一种由人类21号染色体（Hsa21）三体性导致的高度复杂的发育性遗传疾病。所有唐氏综合征患者都表现出一定程度的脑结构变化和认知障碍；诸如Ts65Dn等小鼠模型对于理解其潜在机制起到了重要作用。唐氏综合征的几种表型可能源于三体细胞对音猬因子（SHH）生长因子的反应降低。如果所有三体细胞对SHH都表现出类似的反应降低，那么三体细胞中该信号通路的上调可能会改善多种唐氏综合征表型。我们将Ptch1tm1Mps/+小鼠（由于该信号通路抑制因子Ptch1的一个等位基因功能丧失，预计在每个对SHH有反应的细胞中经典SHH信号通路都会上调）与Ts65Dn唐氏综合征模型进行杂交，并评估后代是否可能挽救多种与唐氏综合征相关的表型。Ptch的下调本身对发育产生了一些先前未报道的影响，使某些表型的解释变得复杂，并且三体的一些结构或行为影响并未通过SHH信号得到补偿。然而，筑巢任务中的缺陷在Ts;Ptch+/-小鼠中部分得到恢复，Ts65Dn小鼠中出现的小脑结构异常也得到了改善。这些结果进一步证明，三体细胞和组织对SHH反应的降低促成了三体表型的各个方面。
