Deceleration and acceleration in the rate of posterior neuropore closure during neurulation in the curly tail (ct) mouse embryo

Summary Curly tail (ct) is a mouse mutant producing spinal neural tube defects as a result of delayed closure of the posterior neuropore (PNP). The purpose of the present study was to determine in ct/ct embryos the time of onset of the delay in PNP closure, and the pattern of this closure, as well as to study the possibility that reopening of the neural tube occurs. Normal spinal neurulation was studied in non-mutant Swiss (Sw) embryos. In the latter, the average PNP length diminished steadily between the 7- and 25-somite stages, and then decreased more rapidly, indicating an acceleration of closure rate, until the 30- to 32-somite stage, when all PNPs closed. PNP width decreased steadily between the stages of 7 and 30 somites. In ct/ct embryos the average PNP length showed a slight increase between the stage of 23 to 28 somites, indicating a temporary deceleration of closure rate, and the range of PNP sizes increased markedly. This was followed by a decrease in PNP length until the 37-somite stage, indicating an acceleration of closure rate. From the stage of 32 somites onwards, the proportion of embryos with closed PNPs gradually increased to 90%. The population of ct/ct embryos was subdivided. Embryos with large PNPs showed a marked deceleration of closure rate during a period of 11 somite stages, followed by a brief but very high acceleration of closure rate. This resulted in closure of the PNP in a proportion of these embryos, while in the remainder of the embryos the deceleration phase had been too enhanced to allow complete catch up of closure during the acceleration phase; these embryos would develop spina bifida. Embryos with relative small PNPs also showed a deceleration of closure rate, but only during a period of four somite stages. This was followed by an acceleration, resulting in closure of all PNPs at the stage of 32 to 33 somites. The enlargement of the PNP in ct/ct embryos was not due to re-opening of a closed neural tube, but resulted from a sharp decline in the rate of PNP closure combined with a normal rate of caudal elongation of the embryo. It is concluded that the ct strain forms a homogeneous population, with a large variation of its specific phenotype: deceleration of PNP closure during a restricted period. The disturbance of spinal neurulation in ct/ct embryos takes the form of a deceleration/acceleration pattern, resulting in a net delay of closure. It is suggested that, due to the ct mutation, forces are generated in the embryonic axis which oppose a normal neurulation process at a specific stage of development.     

PMX诱导神经管畸形及其对神经上皮细胞增殖和凋亡的影响

目的:用培美曲塞(pemetrexed,PMX)建立叶酸缺乏的神经管畸形(neural tube defect,NTD)动物模型,并探讨其对神经上皮细胞增殖和凋亡的影响。方法:应用不同剂量PMX(5、10、15、17.5、20和30 mg/kg)对C57BL/6孕鼠进行干预,筛选最佳造模剂量。采用磷酸化组蛋白H3(pH3免疫组化的方法以及TUNEL方法)观察胎鼠神经上皮增殖和凋亡情况。结果:随着PMX剂量的增加,小鼠胚胎的吸收胎和畸形率逐渐增加,其中17.5mg/kg体重组的NTD的发生率最高(30.6%),被筛选为最佳造模剂量。pH3免疫组化和TUNEL结果显示,与正常对照组相比,NTD小鼠胚胎神经上皮细胞增殖减少(P<0.05),凋亡增加(P<0.05)。结论:PMX能诱导NTD的发生,其机制可能是因为PMX阻断了叶酸代谢通路并导致神经上皮细胞的增殖抑制和过度凋亡。     

p53对体外神经干细胞增殖能力的影响

目的:探讨p53对神经干细胞(neural stem cells,NSCs)增殖能力的影响,寻求维持NSCs活力的有效途径。方法:分离出生后0 d(postnatal day 0,P0)和生后90 d(postnatal day 90,P90)小鼠前脑室管膜下区(subventricular zone,SVZ)组织,培养NSCs。比较P0和P90 NSCs增殖能力并通过q PCR和Western Blot检测衰老相关分子p53和p21在新生和成年NSCs的表达变化。应用p53抑制剂PFT-α(20μmol/L)连续作用于P90 NSCs 72 h,通过Brd U掺入实验和CCK-8实验,分析抑制p53对NSCs增殖能力的影响。结果:随年龄增加,NSCs的增殖能力降低,P90组神经球的数量和直径分别是P0组的22.9%±1.2%(P0.01)和63.5%±3.7%(P0.05)。P90NSCs p53和p21 mRNA表达水平分别较P0 NSCs显著增高了1.4±0.05和1.2±0.04(P0.01)。Western Blot结果证明P90 NSCs p53蛋白的表达水平比P0 NSCs增加了1.2±0.01倍(P0.05)。经p53抑制剂PFT-α连续处理P90 NSCs 72 h后,CCK-8结果显示PFT-α组吸光度值1.1±0.02高于DMSO组0.8±0.03(P0.05),Brd U掺入实验也显示PFT-α组Brd U阳性细胞率为43.3%±4.0%显著高于DMSO组24.8%±3.1%(P0.05)。结论:p53信号通路激活可能是导致成年小鼠NSCs增殖能力下降的重要因素,应用p53抑制剂PFT-α能够增加成年NSCs的增殖能力。     

维甲酸对胎鼠Vangl1及Vangl2基因表达的影响

神经管畸形的发生是由遗传因素与环境因素共同作用产生的。平面细胞极性途径（planar cell polarity，PCP）对脊椎动物神经胚形成非常重要。该途径基因的任何突变都可能导致神经管不能闭合，与人类的颅脊柱裂相似。但是，环境因素是否影响、如何影响PCP途径基因的表达到目前仍不清楚。目的研究维甲酸对胎鼠Vangl1及Vangl2基因表达的时空特征的影响。方法全反式维甲酸橄榄油混悬液按120mg／kg在BALB／C小鼠怀孕第9．5天（E9．5）（B组）或E10．5（C组）灌胃，A组仅用橄榄油灌胃。取E9．5、E10．5、E11．5、E13．5、E15．5、E17．5、E19．5胎鼠，Vangl1及Vangl2基因表达量采用逆转录酶PCR（RT—PCR）检测，其时空表达采用全胚胎原位杂交（WISH）检测。结果结果显示，正常情况下Vangl1及Vangl2基因在整个神经胚形成过程中都有强表达。而B组胎鼠从脑到后神经孔Vangl1及Vangl2基因表达显著下调。C组较复杂，二基因表达在全胚胎（从E11．5到E13．5）及神经管脊柱区（从E15．5到E19．5）显著下调并维持低表达，但在神经管的颅区（E15．5到E19．5）仅中度下调。结论：结果提示，维甲酸诱导的神经管畸形的发生与Vangl1及Vangl2基因转录子下调有关。     

HBx基因缺失型突变体对肝细胞QSG7701细胞增殖和凋亡的影响

目的研究HBx-d382和HBx-d431缺失型突变体对永生化QSG7701肝细胞生物学行为的影响。方法采用HE染色法,观察转染细胞形态学变化,通过MTT、软琼脂克隆形成实验、流式细胞仪及裸鼠成瘤实验研究稳定转染细胞的生物学特性。结果与转染空质粒pcDNA3相比,转染肝癌组织中HBx-d382和HBx-d431突变体及HepG2.2.15细胞株中HBx-2215基因的QSG7701细胞大小形态不一致、体积增大、核浆比例增大,生长速度更快,克隆形成率高（P〈0.05）。与转染空质粒pcDNA3S期百分比（29.4%）和凋亡率（13.1%）比较,pcDNA3/HBx-d382和pcDNA3/HBx-2215组细胞S期百分比比例增高,分别为32.8%和35.0%,pcDNA3/HBx-d431组凋亡率下降（4.5%）。结论 HBx-d382和HBx-d431缺失型突变体能促进QSG7701细胞增殖和恶性转化。     

Effects of an imprinting procedure on cell proliferation in the chick brain

We report here studies on the effects of an imprinting procedure on cell proliferation in neonatal chicks in brain structures known to undergo plastic changes in imprinting. Proliferating cells were detected immunohistochemically on brain sections by incorporation of pre-training doses of 5-bromodeoxyuridine (BrdU) into DNA; numbers of new cells were counted in the intermediate medial mesopallium, the intermediate arcopallium, the medial part of the mesopallium and the nidopallium, the dorsocaudal nidopallium, the hippocampus, and the parahippocampal region 24 h and seven days after training. The intermediate medial mesopallium showed an increase in the number of BrdU-positive cells 24 h after training. However, at seven days post-training, the number of BrdU-containing cells decreased in the medial nidopallium and mesopallium, in the dorsocaudal nidopallium, and the right intermediate medial mesopallium. Thus, the imprinting procedure had differently directed transient and long-term influences on the genesis of new cells in the chick brain, inducing the appearance of a large number of cells in the parenchyma of the brain one day after training and decreases in the numbers of cells at later time points. This double effect may be associated with the fact that the imprinting procedure simultaneously initiates two brain processes involving the control of cell proliferation — one related to maturation of a species-specific functional system for tracking individuals of the same species and one related to remembering the characteristics of the actual parent. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 57, No. 2, pp. 181–190, March–April, 2007.     

低氧对胎鼠中脑NSCs的促体外增殖作用

目的观察低氧对大鼠中脑神经干细胞体外增殖的影响,并探讨其增殖的可能机制。方法取孕13.5 d的W istar大鼠,麻醉后取胚胎,分离中脑神经干细胞(NSC),常规培养鉴定后分3组:对照组;10%O2组;3%O2组。采用4孔板培养3~4 d后进行神经球记数,用流式细胞仪测定其增殖指数,最后用RT-PCR方法测定低氧(10%O2)不同时间点(1、3、6、12、24、48和72 h)低氧诱导因子-1α(HIF-1α)mRNA的表达水平。结果低氧组神经球记数和增殖指数明显高于对照组,尤以10%O2组最为明显(P<0.01);10%O2组12 h和48 h时的HIF-1αmRNA表达水平比同一时间点的对照组明显增加。结论轻中度低氧有利于NSC的体外增殖,而HIF-1可能在其中发挥了重要作用。     

ATF4对皮肤癌细胞增殖的影响及相关机制

目的：探讨沉默/过表达ATF4对人皮肤癌细胞增殖的影响及其相关作用机制。方法：Western blot技术检测不同类型皮肤癌细胞中ATF4的蛋白表达水平。构建ATF4沉默/过表达的A431皮肤癌细胞株,采用CCK-8法、克隆形成实验和流式细胞术检测A431细胞增殖能力的变化及细胞周期分布;Western blot技术检测细胞周期调控因子cyclin D1、cyclin E、P21和p-Rb/Rb的蛋白表达水平。结果：ATF4在3种不同类型的皮肤癌细胞中均呈高表达。CCK-8法和克隆形成实验结果显示沉默ATF4的A431细胞存活率和增殖能力均显著降低(P<0.05),而过表达ATF4可促进A431细胞的增殖;流式细胞仪检测结果显示沉默ATF4可明显抑制A431细胞从G0/G1期向S期转换,过表达ATF4则促进其G1/S转换。同时Western blot实验结果显示沉默ATF4后,cyclin D1、cyclin E和p-Rb的蛋白水平均显著降低,而P21的蛋白表达显著增加(P<0.05),过表达ATF4后则cyclin D1、cyclin E和p-Rb的蛋白水平显著增加,而P21的蛋白表达显著降低(P<0.05)。结论：ATF4能够促进人皮肤鳞状细胞癌细胞株A431的增殖,其潜在作用机制可能与促进细胞周期G1/S转换及影响相关周期调控因子的表达有关,提示AT F 4可作为治疗皮肤癌的一个潜在作用靶点。     

Ultrastructural observations on cell necrosis during formation of the neural tube in mouse embryos

Summary Spontaneous cell death in the developing brain of 8.5–9 day old mouse embryos has been investigated with the electron microscope. Before closure of the neural tube, areas of cell death are found at the neuro-somatic junction. After closure of the neural tube degenerating cells are found in the dorsal midline of the prospective diencephalon. Ultrastructurally, cell degeneration is marked by chromatin condensation, increase in electron density of the structures in the cytoplasm and, in later stages, by a marked pycnosis of the dying cell. After fragmentation, the necrotic material as well as entire pycnotic cells are phagocytized and digested by cells of the neuroepithelium. An invasion of macrophages has not been observed. The significance of cell necrosis is discussed in relation to the normal formation of the neural tube and to the occurrence of certain induced malformations (exencephalies).     

上调miR-143表达对CasKi人宫颈鳞癌细胞系增殖与凋亡的影响

目的探讨miR-143对CasKi宫颈鳞癌细胞增殖与凋亡活性影响。方法应用荧光定量RT-PCR法检测miR-143在人宫颈鳞癌组织中表达水平,以及miR-143在CasKi细胞株中表达水平与变化;人工合成miR-143模拟体转染CasKi宫颈鳞癌细胞系,采用流式细胞技术、MTT等实验方法探讨上调miR-143表达对CasKi癌细胞增殖活性与凋亡影响。结果宫颈鳞癌组织与宫颈鳞癌细胞株CasKi中miR-143表达水平较正常宫颈组织明显下调,其中2例鳞癌组织未能检测出miR-143表达。miR-143 mimics转染组miR-143表达显著高于空白对照组;MTT检测结果表明miR-143 mimics转染组中细胞增殖抑制明显,且抑制效应自转染48 h开始显现。细胞周期检测结果显示miR-143 mimics转染组G0/G1期细胞明显增多,S期细胞减少,组间差异有统计学意义(P0.05)。荧光TUNEL检测结果亦显示miR-143 mimics转染组细胞凋亡率增加(9.45±2.31)%,高于阴性对照组(4.03±1.35)%与空白对照组(3.85±1.61)%,组间差异具有统计学意义(P0.05)。结论上调miR-143表达可抑制宫颈鳞癌细胞增殖活性,影响宫颈鳞癌细胞周期和诱导宫颈鳞癌细胞凋亡。     

靶向PSMB5基因的shRNA慢病毒载体对神经干细胞增殖和分化潜能的影响

目的:优化20S蛋白酶体β5亚单位(proteasome subunit beta type-5,PSMB5)-shRNA慢病毒感染神经干细胞(neural stem cells,NSCs)的方案,观察PSMB5表达下调对NSCs增殖和分化能力的影响,探讨调控NSCs潜能的分子机制。方法:构建携带绿色荧光蛋白(green fluorescent protein,GFP)基因的PSMB5-shRNA慢病毒载体,并设错义序列对照,感染新生小鼠(postnatal day 0,P0)NSCs。倒置荧光显微镜观察GFP阳性率,计算感染率,RT-PCR、免疫印迹和荧光分光光度法检测PSMB5沉默效率和蛋白酶体活性。比较对照组和shRNA组神经球的数量和直径,利用CCK-8实验观察PSMB5基因沉默对NSCs增殖潜能的影响。Tuj1染色观察PSMB5基因沉默对NSCs分化能力的影响。结果:PSMB5-shRNA慢病毒感染NSCs 24 h后可见GFP荧光表达,48 h达峰值,传代后可见GFP稳定表达。其感染复数MOI为40,polybrene 3μg/ml时,感染48 h GFP阳性率可达92.5%±2.3%;PSMB5-shRNA组PSMB5 mRNA和蛋白表达水平分别较对照组降低66.49%±4.81%(P0.001)和33.1%±2.54%(P0.001)。PSMB5-shRNA组蛋白酶体活性较对照组下降43.4%±1.48%(P0.01)。shRNA组NSCs的增殖能力降低,神经球数量为126.5±8.4显著低于对照组163.5±9.5(P0.01),神经球的平均直径为29.9μm±2.6μm显著低于对照组42.9μm±2.3μm(P0.01)。CCK-8结果表明PSMB5-shRNA组细胞吸光度值0.36±0.04,显著低于对照组0.59±0.03(P0.001),PSMB5-shRNA组Tuj1+阳性率为39.13%±8.14%,较对照组显著降低(P0.01)。结论:PSMB5基因沉默可降低NSCs蛋白酶体活性抑制P0期小鼠NSCs增殖分化能力。     

海人酸对神经干细胞增殖及分化的影响

背景：神经干细胞对脑组织的修复作用非常有限,约80%新增殖的内源性神经干细胞在6周内死亡,仅0.2%的细胞继续增殖、分化,参与修复。 目的：分析不同剂量海人酸在对神经干细胞增殖及分化的影响。 方法：体外分离并培养新生Wistar大鼠神经干细胞,将神经干细胞分为空白对照组和加入不同浓度梯度的海人酸组,通过免疫组化法和免疫荧光法进行鉴定,MTT比色法测定海人酸对神经干细胞分化的影响,计算分化后神经元和星形胶质细胞比例。 结果与结论：海人酸组贴壁的神经球分化速度较空白对照组快,在同一时间点进行观察,神经细胞的迁移距离较未处理组远。分化5 d后,海人酸组所分化的细胞中,星状细胞较空白对照组多,而神经元样细胞相对较少,培养的细胞具有自我更新和向神经元﹑少突胶质细胞和星形胶质细胞分化的潜能。兴奋性氨基酸海人酸可使部分神经干细胞死亡,但可促进幸存的神经干细胞增殖及分化,并诱导其向星形胶质细胞分化。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

条件培养液对Wistar大鼠海马神经干细胞单细胞克隆增殖的影响

目的探讨神经干细胞(NSCs)条件培养液对其单细胞克隆增殖的影响。方法采用无血清培养法体外培养Wistar大鼠海马神经干细胞并进行传代培养,然后收集神经干细胞条件培养液。第四代细胞进行单细胞克隆,并将单细胞克隆细胞分为条件培养液组、无血清培养液对照组。通过MTT法比较两组细胞的增殖情况。单克隆培养细胞行巢蛋白(nestin)免疫细胞化学染色,诱导分化后细胞行神经元特异性烯醇化酶(NSE)、胶质原纤维酸性蛋白(GFAP)、半乳糖脑苷脂(Galc)免疫细胞化学染色。结果单克隆培养后克隆球表达nestin,诱导分化后细胞表达NSE、GFAP、Galc,条件培养液组细胞增殖速度高于对照组。结论条件培养液能提高Wistar大鼠海马神经干细胞单细胞克隆的增殖速度。     

Different types of neural cell death in the cerebellum of the ataxia and male sterility (AMS) mutant mouse

To investigate the mechanisms(s) of age-dependent atrophy of the cerebellum of the ataxia and male sterility (AMS) mouse at young age, the morphological changes were evaluated and the nature of neural cell death was examined. Dying Purkinje cells lacked characters of classical apoptosis except for light microscopic morphology, but their death was considered to be autonomous death triggered by the direct effect of ams mutation, because of the acute and near-complete disappearance and particular change of the cytoplasm. In contrast, in the granular layer, typical apoptotic bodies were recognized by electron microscopy, and substantial numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end-labeling (TUNEL)-positive cells and activated caspase-3-positive cells were observed. Granule cell death was considered to be target-related apoptosis induced after post-synaptic Purkinje cell death, because the age-dependent changes in TUNEL-positive cell counts followed that of Purkinje cell loss and the peak value was still noted 1 week after total loss of Purkinje cells. These results indicate that both total and partial losses of Purkinje cells and granule cells, respectively, contributed to the atrophy of the AMS cerebellum. Furthermore, different types of neuronal death were recognized; the granule cell death was apoptotic while Purkinje cell death was different from that of classical apoptosis.     

缓释阿托伐他汀钙纳米纤维支架对细胞黏附增殖的影响

文题释义：去溶剂化法：如果溶胶的溶剂化层和胶粒较强的结合力被破坏,则会导致两者的分离,胶体就会聚沉,这个过程就是去溶剂化过程,一般通过加热或者加入去溶剂化溶剂实现,乙醇是常见制备蛋白微粒的去溶剂化溶剂。 静电纺丝：是一种特殊的纤维制造工艺,高分子聚合物溶液或熔体在强电场中进行喷射纺丝。在电场作用下,针头处的液滴会由球形变为圆锥形(即“泰勒锥”),并从圆锥尖端延展得到纤维细丝,是高分子流体静电雾化的一种形式,在材料学领域已有较为广泛的应用。  摘要背景：他汀类药物在调节血脂、治疗和预防心脑血管疾病方面有显著作用,近些年研究发现他汀类药物在促骨形成及治疗骨质疏松方面具有一定的潜力。 目的：制备牛血清白蛋白微球及聚己内酯静电纺丝双重屏障缓释支架,用于药物阿托伐他汀钙的局部缓释,并探讨药物缓释支架对成骨细胞黏附及增殖的影响。 方法：采用去溶剂化法制备载阿托伐他汀钙的牛血清白蛋白微球,通过静电吸附作用在牛血清白蛋白微球表面包裹一层壳聚糖,达到增加微球稳定性的作用;将壳聚糖稳定的牛血清白蛋白微球纯化并冷冻冻干,备用。将微球冻干粉加入有机溶剂中充分溶解,再加入适当量纳米羟基磷灰石搅拌均匀,利用静电纺丝技术制作缓释阿托伐他汀钙纳米纤维支架,表征支架的微观形貌、降解性能与缓释性能。将缓释阿托伐他汀钙纤维支架与MC3T3-E1细胞共培养,观察细胞的黏附与增殖。结果与结论：①透射电镜显示,牛血清白蛋白纳米微球为规整的圆形,分散在静电纺丝中,其微球的基本形态得到保留;②扫描电镜显示,缓释阿托伐他汀钙纳米纤维支架的纳米纤维由直径均匀且表面连续光滑的丝构成,细丝交织形成网状结构;③缓释阿托伐他汀钙纳米纤维支架第1个月降解速度最快,后期降解速度减缓,降解3个月时材料已经不完整;④缓释阿托伐他汀钙纳米纤维支架有缓慢缓释药物的性能,时间长达1个月以上,总体释放类似零级动力学过程;⑤缓释阿托伐他汀钙纳米纤维支架可促进MC3T3-E1细胞的黏附与增殖;⑥结果表明,缓释阿托伐他汀钙纳米纤维支架具有良好的生物相容性,可促进成骨细胞的增殖与黏附。ORCID: 0000-0003-3316-061X(王乐) 中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

妊娠期糖尿病中胎盘外泌体对滋养细胞增殖、细胞周期及凋亡的影响

目的：探讨妊娠期糖尿病（GDM）中胎盘外泌体对滋养细胞增殖、细胞周期及细胞凋亡的影响。方法： 选取2018 年3 月至2019 年4 月间重庆市第七人民医院50 例诊断为GDM患者（GDM组）,另选取50 例正常孕产 妇作为对照组。分离纯化GDM组和对照组孕产妇外周血血浆中的胎盘外泌体,通过透射电镜观察外泌体的形 态,纳米粒径分析检测外泌体的直径,免疫印迹检测外泌体标志性蛋白CD63、TSG101 及胎盘标志性分子胎盘 碱性磷酸酶（PLAP）的表达。PKH67染色后荧光共聚焦显微镜观察体外培养滋养细胞系对外泌体的摄取情况; 应用MTT实验检测外泌体对滋养细胞增殖能力的影响,流式细胞术检测外泌体对滋养细胞周期的影响,Annexin V-FITC/PI 双染色结合流式细胞术检测外泌体对滋养细胞凋亡的影响。结果：成功从外周血中分离获得了胎盘外 泌体,形态呈典型的杯状或双凹状,直径为40 ～ 120 nm,CD63、TSG101、PLAP 表达呈阳性;与对照组相比, GDM组胎盘外泌体以浓度依赖性促进滋养细胞的增殖、细胞周期进展,并抑制滋养细胞的凋亡。结论：GDM中 胎盘外泌体可能通过促进滋养细胞的增殖、细胞周期进展,抑制滋养细胞凋亡等参与GDM的发生和发展。     

Effects of age and strain on cell proliferation in the mouse rostral migratory stream

The number of neural progenitor cells (NPCs) decreases with advancing age, and the mechanisms responsible for this decline is unclear. Here, we demonstrate the importance of genetics as a modulator for the age-related decline in NPCs. We systematically quantified the number of proliferating NPCs in the rostral migratory stream, the rostral extension of the subventricular zone, in 9 inbred mouse strains from 3 to 18 months of age. A striking negative impact of age and significant interstrain differences in the number of NPCs was detected at 3 and 12 months of age. Extended proliferative profiles of C57BL/6J and DBA/2J from 3 to 24 months of age revealed differential dynamics of the age-related decline in NPCs. Statistically significant interaction effects for age and strain were detected over the 3- to 7-month period. Strain differences were mapped to several genetic loci suggesting complex genetic control of NPC proliferation at different ages. Furthermore, correlational analyses revealed the differential regulation of cell proliferation and genes that may underlie the proliferative deficits of NPCs in the aging brain.