Mechanisms of Sex Determination in Zebrafish

斑马鱼性别决定机制

• 批准号: 7890256
• 负责人: JOHN H. POSTLETHWAIT
• 金额: $ 26.16万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890256
• 关键词: Address; Adolescent; Affect; Aromatase; Biological; Cell Count; Cell Death; Cues; DNA Repair; Developed Countries; Development; Disease; Environment; Environmental Risk Factor; Enzymes; Equilibrium; Estrogens; Female; Fishes; Gene Expression Profile; Genes; Genetic; Genotype; Germ Cells; Gonadal structure; Hormones; Human; Individual; Investigation; Learning; Link; Malignant neoplasm of testis; Mammals; Maps; Meiosis; Methodology; Modeling; Molecular Genetics; Mutation; Nature; Oocytes; Organ; Orthologous Gene; Ovary; Pathway interactions; Pattern; Phenotype; Polycystic Ovary Syndrome; Population; Pregnancy; Production; Receptor Gene; Reproductive Health; Role; Sex Bias; Sex Differentiation; Sexual Development; Siblings; Signal Transduction; Somatic Cell; Sterility; Steroid Receptors; Structure of primordial sex cell; Supporting Cell; Syndrome; System; Temperature; Testicular Dysgenesis Syndrome; Testing; Testis; Testosterone; Tretinoin; Uterus; Vertebrates; Woman; Work; Y Chromosome; Zebrafish; gene function; genetic sex determination; genome sequencing; genome-wide; in utero; innovation; insight; male; men; mutant; public health relevance; reproductive; research study; sex; sex determination; social; tool; trait

DESCRIPTION (provided by applicant): Human reproductive health depends on gonad development, which can be adversely affected in utero by unknown genetic and environmental factors. In mammals, the Y-chromosome gene SRY initiates an incompletely understood network that directs the gonad to become a testis rather than an ovary. In nonmammalian vertebrates, other genes in the network determine sex, and in some species, environmental factors such as temperature or social cues can bias sex development. This project's broad objective is to learn how genetic factors, interacting with the environment, can tip the balance towards one sex or another. Work focuses on zebrafish, a genetically tractable vertebrate in which sex determination can be easily tipped in one direction or the other. The zebrafish gonad initially develops as a bipotential organ, with a few primordial germ cells in all juveniles initially developing as oocytes. In some individuals, oocytes die and the gonad becomes a testis; in others, oocytes survive and the gonad becomes an ovary. A key question is, what genetic or environmental signals cause presumptive oocytes to die in some individuals and to survive in others? An important tool to probe this question is a recessive mutation in fancl that causes female-to-male sex reversal. Preliminary experiments show excess cell death in homozygous mutant juvenile gonads and suggest the hypothesis that 1) environmental and genetic factors affect oocyte survival in juveniles, and thereby 2) alter the strength of an oocyte-derived signal that promotes, in surrounding somatic cells, 3) the production of aromatase, the enzyme that 4) converts testosterone to estrogen, which preserves oocytes and biases the gonad toward a female fate; 5) with insufficient quantities of the hypothesized oocyte-derived signal, the gonad becomes a testis. Aim 1 is to identify genetic factors linked to sex phenotype in F2 mapping crosses. Aim 2 is to conduct a genome-wide search for genes expressed sex specifically by comparing transcriptomes of all-male populations of zebrafish and medaka, a species with genetic sex determination, to female-containing sibling populations (Aim 2a) and to investigate expression patterns of candidate sex determination genes, steroid receptor genes, and extracell signaler genes (Aim 2b). Aim 3 is to test additional components of the hypothesis by learning whether blocking the retinoic acid signal for entry into meiosis can cause sex reversal (Aim 3a) and whether primordial germ cell number controls sex development in zebrafish and medaka (Aim 3b). The proposed work has significance for it's potential to identify new genes and new gene functions by comparing a vertebrate with a delicate balance for sex differentiation (zebrafish) to one with a known genetic male determinant (medaka). Results will contribute to a better understanding of the molecular genetic nature of the vertebrate sex-balance mechanism, and thus contribute to our understanding of possible mechanisms for the current increase in human reproductive disease, including testicular dysgenesis syndrome and polycystic ovary syndrome increasingly observed in developed countries. PUBLIC HEALTH RELEVANCE: Understanding the biological mechanisms that tip the balance of sex determination between male and female is essential to understand recent increases in human reproductive disorders originating in the womb, including sterility and testis cancer in men and polycystic ovary syndrome in women. Certain genetic make- ups may be especially prone to disruption. Investigations of vertebrate species with finely balanced sex determination mechanisms may provide insight into how environmental and genetic factors tip the sex determination balance in humans. Although many features of zebrafish gonad development are similar to those in humans, zebrafish sex determination is more labile; furthermore, in zebrafish, genetic tools are available to dissect the mechanisms of sex determination, which should identify new genes and new gene functions relevant for human reproductive health.

描述（由申请人提供）：人类生殖健康取决于性腺发育，在子宫内可能会受到未知的遗传和环境因素的不利影响。在哺乳动物中，Y染色体基因启动了一个不完全理解的网络，该网络指导性腺成为睾丸而不是卵巢。在非哺乳动物脊椎动物中，网络中的其他基因决定了性别，在某些物种中，温度或社会提示等环境因素会偏向性别发展。该项目的广泛目标是了解遗传因素与环境相互作用，如何将平衡倾向于一种或另一种性别。工作重点是斑马鱼，斑马鱼是一种遗传拖延的脊椎动物，可以轻松地朝着一个方向或另一个方向倾斜性别。斑马鱼的性腺最初是作为双势器官发展而成的，在所有幼体中，最初都以卵母细胞的形式出现了一些原始生殖细胞。在某些人中，卵母细胞死亡，性腺变成睾丸。在其他情况下，卵母细胞生存，性腺成为卵巢。一个关键问题是，哪些遗传或环境信号会导致某些人死亡并在其他人中生存？探究这个问题的一个重要工具是幻想中的隐性突变，会导致女性到男女的性逆转。初步实验表明，纯合突变幼虫性腺中的细胞死亡过多，并表明假设：1）环境和遗传因素会影响青少年的卵母细胞存活，2）因此改变了卵母细胞衍生信号的强度使性腺偏向女性命运； 5）性腺具有不足的假设卵母细胞衍生的信号，成为睾丸。目的1是确定与F2映射十字中的性表型相关的遗传因素。 AIM 2是通过比较具有遗传性别确定的物种的全男种群的转录组，与含女性的同胞种群（AIM 2A）和研究候选性别确定基因的表达模式，类固醇受体基因，类固醇信号基因和AIM基因（AIM Signaler Genes（AIM Signaler Genes）（AIM Signaler Genes（AIM Signaler Genes）（AIM 2B），AIM 2是针对全基因组进行全基因组搜索。 AIM 3是通过学习阻止视黄酸信号进入减数分裂来检验假设的其他组成部分（AIM 3A）以及原始生殖细胞数是否控制斑马鱼和Medaka的性发展（AIM 3B）。提出的工作具有重要的意义，因为它的潜力通过将脊椎动物与性别分化的微妙平衡（斑马鱼）与具有已知遗传性雄性决定因素（MEDAKA）的脊椎动物进行比较。结果将有助于更好地理解脊椎动物性别平衡机制的分子遗传性质，从而有助于我们理解人类生殖疾病当前增加的可能机制，包括睾丸发育不全综合征和多囊性卵巢综合征在发达国家越来越多地观察到。 公共卫生相关性：了解男性和女性之间的性别确定平衡的生物学机制对于了解源自子宫内的人类生殖疾病的最新增加至关重要，包括男性的不育和睾丸癌和女性多囊卵巢综合征。某些基因组成可能特别容易受到干扰。对具有微妙的性别确定机制的脊椎动物进行的研究可能会深入了解环境和遗传因素如何使人类的性别确定平衡。尽管斑马鱼性腺发育的许多特征与人类的发展相似，但斑马鱼的性别确定更加不稳定。此外，在斑马鱼中，可以使用遗传工具来剖析性别确定的机制，这些机制应鉴定出与人类生殖健康相关的新基因和新基因功能。