BACKGROUND Down syndrome (DS), caused by the triplication of chromosome 21, results in a constellation of clinical features including changes in intellectual and motor function. Although altered neural development and function have been well described in people with DS, few studies have investigated the etiology underlying the observed motor phenotypes. Here, we examine the development, patterning, and organization of the spinal cord throughout life in the Ts65Dn mouse, a model that recapitulates many of the motor changes observed in people with DS. METHODS Spinal cords from embryonic to adult animals were processed for gene and protein expression (immunofluorescence) to track the spatiotemporal development of excitatory and inhibitory neurons and oligodendroglia. Postnatal analyses were focused on the lumbar region due to the reflex and gait abnormalities found in Ts65Dn mice and locomotive alterations seen in people with DS. RESULTS Between embryonic days E10.5 and E14.5, we found a larger motor neuron progenitor domain in Ts65Dn animals containing more OLIG2-expressing progenitor cells. These disturbed progenitors are delayed in motor neuron production but eventually generate a large number of ISL1+ migrating motor neurons. We found that higher numbers of PAX6+ and NKX2.2+ interneurons (INs) are also produced during this time frame. In the adult lumbar spinal cord, we found an increased level of Hb9 and a decreased level of Irx3 gene expression in trisomic animals. This was accompanied by an increase in Calretinin+ INs, but no changes in other neuronal populations. In aged Ts65Dn animals, both Calbindin+ and ChAT+ neurons were decreased compared to euploid controls. Additionally, in the dorsal corticospinal white matter tract, there were significantly fewer CC1+ mature OLs in 30- and 60-day old trisomic animals and this normalized to euploid levels at 10-11 months. In contrast, the mature OL population was increased in the lateral funiculus, an ascending white matter tract carrying sensory information. In 30-day old animals, we also found a decrease in the number of nodes of Ranvier in both tracts. This decrease normalized both in 60-day old and aged animals. CONCLUSIONS We show marked changes in both spinal white matter and neuronal composition that change regionally over the life span. In the embryonic Ts65Dn spinal cord, we observe alterations in motor neuron production and migration. In the adult spinal cord, we observe changes in oligodendrocyte maturation and motor neuron loss, the latter of which has also been observed in human spinal cord tissue samples. This work uncovers multiple cellular perturbations during Ts65Dn development and aging, many of which may underlie the motor deficits found in DS.

中文翻译：

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唐氏综合征的Ts65Dn小鼠模型中脊神经和胶质细胞群体的时空发育。

背景技术由21号染色体的三倍重复引起的唐氏综合症（DS）导致一系列临床特征，包括智力和运动功能的改变。尽管在DS患者中已经很好地描述了神经发育和功能改变，但很少有研究调查观察到的运动表型的病因。在这里，我们研究了Ts65Dn小鼠一生中脊髓的发育，模式和组织，该模型概括了在DS患者中观察到的许多运动变化。方法处理从胚胎到成年动物的脊髓的基因和蛋白质表达（免疫荧光），以追踪兴奋性和抑制性神经元和少突胶质细胞的时空发育。由于Ts65Dn小鼠的反射和步态异常以及DS患者的机车改变，产后分析的重点是腰椎区域。结果在胚胎E10.5和E14.5天之间，我们在包含更多表达OLIG2的祖细胞的Ts65Dn动物中发现了更大的运动神经元祖域。这些受干扰的祖细胞运动神经元的产生被延迟，但最终产生大量ISL1 +迁移的运动神经元。我们发现，在此时间段内还会产生更多数量的PAX6 +和NKX2.2 +中间神经元（IN）。在成年的腰脊髓中，我们发现三体动物中Hb9水平升高而Irx3基因表达水平降低。这伴随着钙调蛋白+ INs的增加，但其他神经元群体没有变化。在Ts65Dn年龄较大的动物中，与整倍体对照相比，Calbindin +和ChAT +神经元均减少。此外，在背侧皮质脊髓白质束中，在30天和60天大的三体动物中，CC1 +成熟OL明显减少，并且在10-11个月时标准化为整倍体水平。相比之下，成熟的OL种群在侧耳中增加，这是一种携带感觉信息的上升的白质束。在30天大的动物中，我们还发现两个管道中Ranvier结节的数量均减少。在60日龄和成年动物中，这种下降均正常化。结论我们显示出在整个生命周期中区域性变化的脊髓白质和神经元组成的显着变化。在胚胎Ts65Dn脊髓中，我们观察到运动神经元产生和迁移的变化。在成人脊髓中 我们观察到少突胶质细胞成熟和运动神经元丢失的变化，后者在人类脊髓组织样本中也已观察到。这项工作揭示了Ts65Dn发育和衰老过程中的多种细胞扰动，其中许多可能是DS中发现的运动缺陷的基础。