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Dmrt1 in gonadal sex maintenance

Dmrt1 在性腺性别维持中的作用

基本信息

批准号：
8522954
负责人：
Robin E. Lindeman
金额：
$ 5.22万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/8522954
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 social stem tool transcription factor transcriptome sequencing transdifferentiation

项目摘要

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(申请人提供)：性腺组织的适当分化是正常睾丸和卵巢发育的先决条件，而这反过来又是成功的有性繁殖所必需的。在哺乳动物中，双潜能胎儿性腺中的性染色体(XX或XY)决定性别，并决定是否表达促进男性或女性命运的基因。随之而来的性别分化过程在发育早期开始，并在青春期结束。当分化失败时，由此产生的临床疾病可能会使人虚弱。由不规律性分化引起的先天性疾病(也称为性发育障碍，或DSD)涉及完全或部分性反转，导致性腺发育不全，并可能增加患特定类型癌症的风险(Looijenga等人，2007年)。已经发现了几个性调节基因(Tannour-Louet等人，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DMRT1。含有DMRT1的人类染色体9p区域的缺失会导致睾丸发育不全和性反转表型(McDonald等人，1997；Raymond等人，1999)，而缺乏DMRT1的雄性小鼠也会出现类似的性腺组织异常(Raymond等人，2000)。直到最近，人们才开始意识到性别分化不是一个单向的过程。事实上，体细胞性命运活跃地维持在成人性腺中。Zarkower/Bardwell研究小组最近发现，DMRT1对于小鼠睾丸的这种维持程序是必不可少的。DMRT1的缺失导致男性到女性细胞命运的重新编程，睾丸细胞转分化形成卵巢细胞(Matson等人，2011年)。此外，初步研究表明，在成年卵巢中异位DMRT1的存在足以引起广泛的雌雄转分化。总而言之，这些结果表明DMRT1锚定了男性性别维持系统。这项研究培训计划的目标是详细定义由DMRT1控制的基因网络，该网络调控性腺中的性别转分化和性别维持。为了实现这一目标，将采用条件基因敲除和基因激活、RNA-seq表达谱分析和体内病毒转导RNAi等技术。结合使用精确的基因操作和强大的基因组技术，将有助于发现基因功能，并有助于确定控制性细胞命运所必需的调控机制。这一建议的目的是：1)确定控制出生后性腺转分化和男性性别维持的基因网络；2)确定异位DMRT1表达如何使女性性腺组织男性化。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、不孕症和性腺癌的诊断和治疗直接相关。