Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.

Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.     

Cellular interactions in haematopoiesis.

In vitro culture of haematopoietic cells has provided some surprising insights into critical interactions of blood-forming cells. Subpopulations of lymphoid cells have been shown to produce colony-stimulating activity, to interact with macrophages, and to have important effects on the very early stages of erythropoiesis. Macrophages have multiple influences on the proliferation and differentiation of other haematopoietic cells.     

Female fur seals show active choice for males that are heterozygous and unrelated

Much debate surrounds the exact rules that influence mating behaviour, and in particular the selective forces that explain the evolution of female preferences. A key example is the lek paradox, in which female choice is expected rapidly to become ineffective owing to loss of additive genetic variability for the preferred traits. Here we exploit a remarkable system in which female fur seals exert choice by moving across a crowded breeding colony to visit largely static males. We show that females move further to maximize the balance between male high multilocus heterozygosity and low relatedness. Such a system shows that female choice can be important even in a strongly polygynous species, and at the same time may help to resolve the lek paradox because heterozygosity has low heritability and inbreeding avoidance means there is no single 'best' male for all females.     

人参皂苷 Rb1 干预 DSS 诱导结肠炎模型小鼠转录组高通量测序及分析

摘要:目的 研究人参皂苷 Rb1 干预葡聚糖硫酸钠盐( Dextran Sulfate Sodium Salt,DSS)诱导结肠炎模型小鼠转录组学信息特征。 方法 C57BL / 6 雄性小鼠构建动物模型,将 15 只小鼠分为正常组、模型组和 Rb1 组,每组 5 只。 模型组和 Rb1 组给予 4% DSS 并自由饮水,第 2 天给 Rb1 组 40 mg / kg Rb1 进行干预。 持续 9 d,处死小鼠后,取结肠组织。 利用 Illumina 高通量测序平台分别对三组小鼠结肠组织进行转录组测序。 利用测定的转录组学数据对 Rb1 组和模型组两两比较之后进行重叠分析,筛选差异基因进行 GO 和 KEGG 分析。 结果 Rb1 干预后各项指标均有改善;GO 富集后其有 10 450 个有效差异表达基因得到 GO 注释,其中分子功能占 13. 5% ,生物过程占 68. 73% ,细胞组成占 17. 77% ;富集最显著的前 20 个 KEGG 通路中与 Rb1 干预后密切相关的有钙离子信号通路、神经活动配体-受体相互作用通路以及 cAMP 信号通路。 结论 人参皂苷 Rb1 能够缓解 DSS 诱导结肠炎模型小鼠的症状。 通过构建 Rb1 干预后 DSS 诱导结肠炎模型小鼠结肠组织转录组序列数据库,为以后 Rb1 功能基因的挖掘和参与代谢途径提供数据支撑,为临床应用提供新的思路。     

CUMS+LPS致小鼠抑郁模型的建立及人参皂苷Rb1的抗抑郁机制研究

采用慢性轻度不可预知刺激(CUMS)+内毒素(LPS)制备小鼠抑郁模型,并研究人参皂苷Rb1的抗抑郁作用及其机制.将C57BL/6J小鼠随机分为正常对照组、模型组、米诺环素(20 mg/kg)组、Rb1低、中、高剂量(5、10、20 mg/kg)组.模型与给药组小鼠每天给予CUMS刺激,正常组小鼠不予刺激.同时各组小鼠腹腔注射给予相应药物和溶媒,每天1次,共11 d;末次给药1 h后腹腔给予LPS 200μg/kg,24 h后检测相应指标.结果表明:人参皂苷Rb1能显著缩短抑郁小鼠悬尾不动时间(TST)与强迫游泳不动时间(FST),降低血清ACTH和CORT水平及炎症因子TNF-α浓度;能逆转抑郁小鼠海马BDNF表达减少.结果提示:CUMS+LPS能成功诱导小鼠抑郁模型;人参皂苷Rb1能显著改善模型小鼠的抑郁状态,机制可能与调控下丘脑-垂体-肾上腺轴过度兴奋、抑制炎症反应有关.     

Repair deficient human disorders and cancer.

The analysis of the repair of damage to DNA in mammalian cells leads not only to a knowledge of which environmental agents are deleterious to living creatures, but also to an understanding of which reaction products in DNA are potentially carcinogenic and which tissues are the more sensitive.     

Congenital heart disease in mice deficient for the DiGeorge syndrome region.

The heterozygous chromosome deletion within the band 22q11 (del22q11) is an important cause of congenital cardiovascular defects. It is the genetic basis of DiGeorge syndrome and causes the most common deletion syndrome in humans. Because the deleted region is largely conserved in the mouse, we were able to engineer a chromosome deletion (Df1) spanning a segment of the murine region homologous to the human deleted region. Here we describe heterozygously deleted (Df1/+) mice with cardiovascular abnormalities of the same type as those associated with del22q11; we have traced the embryological origin of these abnormalities to defective development of the fourth pharyngeal arch arteries. Genetic complementation of the deletion using a chromosome duplicated for the Df1 DNA segment corrects the heart defects, indicating that they are caused by reduced dosage of genes located within Df1. The Df1/+ mouse model reveals the pathogenic basis of the most clinically severe aspect of DiGeorge syndrome and uncovers a new mechanism leading to aortic arch abnormalities. These mutants represent a mouse model of a human deletion syndrome generated by chromosome engineering.     

Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.     

Effects of an Rb mutation in the mouse.

The retinoblastoma gene is mutated in several types of human cancer and is the best characterized of the tumour-suppressor genes. A mouse strain has been constructed in which one allele of Rb is disrupted. These heterozygous animals are not predisposed to retinoblastoma, but some display pituitary tumours arising from cells in which the wild-type Rb allele is absent. Embryos homozygous for the mutation die between days 14 and 15 of gestation, exhibiting neuronal cell death and defective erythropoiesis.     

Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Members of the muscarinic acetylcholine receptor family (M1-M5) have central roles in the regulation of many fundamental physiological functions. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands. Here we show that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3R-/- mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice. However, M3R-/- mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.     

Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme.

Heparin is a sulphated polysaccharide, synthesized exclusively by connective-tissue-type mast cells and stored in the secretory granules in complex with histamine and various mast-cell proteases. Although heparin has long been used as an antithrombotic drug, endogenous heparin is not present in the blood, so it cannot have a physiological role in regulating blood coagulation. The biosynthesis of heparin involves a series of enzymatic reactions, including sulphation at various positions. The initial modification step, catalysed by the enzyme glucosaminyl N-deacetylase/N-sulphotransferase-2, NDST-2, is essential for the subsequent reactions. Here we report that mice carrying a targeted disruption of the gene encoding NDST-2 are unable to synthesize sulphated heparin. These NDST-2-deficient mice are viable and fertile but have fewer connective-tissue-type mast cells; these cells have an altered morphology and contain severely reduced amounts of histamine and mast-cell proteases. Our results indicate that one site of physiological action for heparin could be inside connective-tissue-type mast cells, where its absence results in severe defects in the secretory granules.     

Diabetes mellitus and genetically programmed defects in beta-cell function.

The pathways that control insulin secretion and regulate pancreatic beta-cell mass are crucial in the development of diabetes mellitus. Maturity-onset diabetes of the young comprises a number of single-gene disorders affecting pancreatic beta-cell function, and the consequences of mutations in these genes are so serious that diabetes develops in childhood or adolescence. A genetic basis for the more common form of type 2 diabetes, which affects 10-20% of adults in many developed countries, is less clear cut. It is also characterized by abnormal beta-cell function, but other tissues are involved as well. However, in both forms identification of causative and susceptibility genes are providing new insight into the control of insulin action and secretion, as well as suggesting new treatments for diabetes.     

Extra-embryonic function of Rb is essential for embryonic development and viability

The retinoblastoma (Rb) gene was the first tumour suppressor identified. Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis and widespread developmental defects, leading to embryonic death by day 14.5 (refs 2-4). However, the actual cause of the embryonic lethality has not been fully investigated. Here we show that loss of Rb leads to excessive proliferation of trophoblast cells and a severe disruption of the normal labyrinth architecture in the placenta. This is accompanied by a decrease in vascularization and a reduction in placental transport function. We used two complementary techniques-tetraploid aggregation and conditional knockout strategies-to demonstrate that Rb-deficient embryos supplied with a wild-type placenta can be carried to term, but die soon after birth. Most of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-null animals were virtually absent in rescued Rb-null pups. These findings identify and define a key function of Rb in extra-embryonic cell lineages that is required for embryonic development and viability, and provide a mechanism for the cell autonomous versus non-cell autonomous roles of Rb in development.