Dmrt1 in gonadal sex maintenance

Dmrt1 在性腺性别维持中的作用

• 批准号: 8651764
• 负责人: Robin E. Lindeman
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-08 至 2016-04-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651764
• 关键词: Address; Adult; Affect; Alleles; Biological Models; Cells; Clinical; Complement; Development; Diagnosis; Diagnostic; Disease; Female; Fertility; Gene Activation; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genomics; Germ Cells; Glean; Goals; Gonadal Disorders; Gonadal Dysgenesis; Gonadal structure; Health; Human; Human Chromosomes; Infertility; Link; Maintenance; Malignant Neoplasms; Mammals; Mediator of activation protein; Molecular; Molecular Genetics; Molecular Profiling; Mus; Ovarian; Ovary; Phenotype; Play; Ploidies; Predisposition; Process; Puberty; RNA Interference; Reagent; Regulator Genes; Reproduction; Research; Research Training; Risk; Role; Sex Chromosomes; Sex Differentiation; Sex Differentiation Disorders; Sexual Development; Somatic Cell; System; Technology; Testis; Tissues; Translating; Vertebrates; Viral; Work; base; cancer type; fetal; gene function; genetic manipulation; gonadal cancer; improved; in vivo; insight; knockout gene; male; mouse model; postnatal; prevent; programs; public health relevance; sex; sex development disorder; social; stem; tool; transcription factor; transcriptome sequencing; transdifferentiation

DESCRIPTION (provided by applicant): Proper differentiation of gonadal tissues is a prerequisite for normal testis and ovarian development, which is in turned required for successful sexual reproduction. In mammals, the complement of sex chromosomes (XX or XY) in the bipotential fetal gonadal determines sex and dictates whether male or female- fate promoting genes are expressed. The consequent sexual differentiation process is initiated early in development and concludes in puberty. When differentiation fails, the resulting clinical disorders can be debilitating. Congenital conditions stemming from irregular sexual differentiation (also known as disorders of sexual development, or DSD) involve complete or partial sex-reversal leading to gonadal dysgenesis and a potentially increased risk of specific types of cancers (Looijenga et al., 2007). Several sex-regulatory genes have been discovered (Tannour-Louet et al., 2010), but the genetic basis of most DSD cases remains unknown. One likely player is the conserved transcription factor Dmrt1. Deletions of the human chromosome 9p region containing DMRT1 cause testicular dysgenesis and sex reversal phenotypes (McDonald et al., 1997; Raymond et al., 1999), and male mice lacking Dmrt1 develop similarly abnormal gonadal tissues (Raymond et al., 2000). Only recently has it begun to be appreciated that sex differentiation is not a unidirectional process. In fact, somatic cell sexual fates are actively maintained in the adult gonads. The Zarkower/Bardwell group recently discovered that Dmrt1 is essential for this maintenance program in the mouse testis. Loss of Dmrt1 results in male-to-female cell fate reprogramming, with testicular cells transdifferentiating to form their ovarian counterparts (Matson et al., 2011). Moreover, preliminary studies indicate that the presence of ectopic DMRT1 in the adult ovary is sufficient to cause extensive female-to-male transdifferentiation. Together these results suggest that Dmrt1 anchors the male sex maintenance system. The goal of this research training proposal is to define, in detail, the genetic networks controlled by Dmrt1 which regulate sexual transdifferentiation and sex maintenance in the gonad. To achieve this goal, technologies including conditional gene knockout and gene activation, expression profiling by RNA-seq, and RNAi by in vivo viral transduction in the testis will be employed. Use of a combination of precise genetic manipulations and powerful genomic technologies will facilitate the discovery of gene functions and help define the regulatory mechanisms essential for control of sexual cell fate. The Aims of this proposal are to: 1) identify gene networks that control transdifferentiation and male sex maintenance in the postnatal gonad, and 2) determine how ectopic DMRT1 expression masculinizes female gonadal tissues. The findings from this work should have direct relevance to other examples of cell fate reprogramming and to the diagnosis and treatment of human DSD, infertility, and gonadal cancers.

描述（由申请人提供）：性腺组织的适当分化是睾丸和卵巢正常发育的先决条件，这反过来又是成功的有性生殖所必需的。在哺乳动物中，双能胎儿性腺中的性染色体（XX或XY）的互补决定了性别，并决定了男性或女性命运促进基因的表达。随后的性分化过程在发育早期开始，并在青春期结束。当分化失败时，所产生的临床病症可能使人衰弱。源于不规则性分化的先天性病症（也称为性发育障碍或DSD）涉及导致性腺发育不全的完全或部分性逆转和特定类型癌症的潜在增加的风险（Looijenga等人，2007年）。已经发现了几种性别调节基因（Tannour-Louet et et al.，2010年），但大多数DSD病例的遗传基础仍然未知。一个可能的参与者是保守的转录因子Dmrt 1。含有DMRT 1的人染色体9 p区域的缺失导致睾丸发育不全和性逆转表型（McDonald等人，1997; Raymond等人，1999），而缺乏Dmrt 1的雄性小鼠发育出类似的异常性腺组织（Raymond等人，2000年）。直到最近才开始认识到性别分化不是一个单向的过程。事实上，体细胞的性命运在成年性腺中积极维持。Zarkower/Bardwell小组最近发现，Dmrt 1对小鼠睾丸中的这种维持程序至关重要。Dmrt 1的缺失导致雄性至雌性细胞命运重编程，其中睾丸细胞转分化以形成其卵巢对应物（马特森等人，2011年）。此外，初步研究表明，异位DMRT 1在成年卵巢中的存在足以引起广泛的女性到男性的转分化。这些结果共同表明，Dmrt 1锚定男性性维持系统。这项研究培训计划的目标是详细定义由Dmrt 1控制的遗传网络，该网络调节性腺中的性转分化和性别维持。为了实现这一目标，将采用包括条件基因敲除和基因激活、通过RNA-seq的表达谱分析和通过睾丸中的体内病毒转导的RNAi的技术。精确的遗传操作和强大的基因组技术相结合的使用将促进基因功能的发现，并有助于确定控制性细胞命运所必需的调控机制。该提议的目的是：1）鉴定控制出生后性腺中的转分化和雄性性维持的基因网络，以及2）确定异位DMRT 1表达如何使雌性性腺组织雄性化。这项工作的发现应该与细胞命运重编程的其他例子以及人类DSD，不育症和性腺癌的诊断和治疗直接相关。