Regulation of Follistatin Expression by Activin

激活素对卵泡抑素表达的调节

基本信息

批准号：
8609492
负责人：
Louise M Bilezikjian
金额：
$ 35.55万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8609492
关键词：
Activins Adult Affect Animals Anterior Pituitary Gland Binding Biochemical Biological Availability Birth Blepharophimosis Boxing Cell Line Cell physiology Cells Complex Defect Development Dominant-Negative Mutation Embryo Endocrine Endocrine System Diseases Exhibits Eyelid structure FSH Cell Family Feedback Female Follistatin Funding Genes Genetic Models Genetic Transcription Glycoproteins Gonadal Steroid Hormones Gonadotropins Grant Growth Factor Hereditary Disease In Vitro Infertility Knock-out Knockout Mice LH Cell Ligands Mediating Mediator of activation protein Modeling Molecular Target Mus Mutagenesis Mutant Strains Mice Ovarian Pathology Patients Phenotype Pituitary Gland Play Premature Ovarian Failure Proteins Proteomics Ptosis Regulation Reporting Research Proposals Role Series Signal Transduction Small Interfering RNA Syndrome Technology Testing Tissues Transcript Woman autocrine cell type design forkhead protein human tissue immunoreactivity in vitro Model in vivo in vivo Model inhibin loss of function mutation male malformation member mutant novel paracrine prevent programs protein protein interaction ptosis epicanthus syndrome public health relevance reproductive reproductive function research study response

项目摘要

DESCRIPTION (provided by applicant): The objective of this research proposal is to gain an understanding of the mechanisms underlying cell-type specific actions of activin on key targets of pituitary gonadotropes. Activins are pleiotropic regulators of diverse tissues and cellular functions, often acting through autocrine/paracrine mechanisms. They play a critical role in the pituitary to locally regulate gonadotrope function and promote the differential expression and secretion of the two gonadotropins, FSH and LH. Follistatins are secreted glycoproteins that function extracellularly to bind and modulate the local bioavailability of activin and other related ligands of the TGF-¿ family through a feedback loop. In the pituitary, as in other tissues, the precise control of the activin/follistatin network helps maintain the functional integrity of target cells and prevents the development of pathologies. The dynamic control of activin/follistatin tone is achieved by the reciprocal actions of activin and follistatin and the self- modulating action of activin that exerts control on follistatin expression. Genetic models have substantiated the importance of follistatin by demonstrating that mice null for follistatin exhibit many embryonic defects and die shortly after birth while follistatin over-expression is associated with varying degrees of infertility. The follistatin gene is a transcriptional target of activin. In gonadotropes, this effect is mediated through the coordinated actions of the activin mediator, Smad3, and a member of the forkhead family of transcription factors, FoxL2. Functional and biochemical experiments have illustrated that FoxL2 is an obligatory partner of Smad3 for activin-dependent transcription of the follistatin gene in gonadotrope-derived cell types. FoxL2 is expressed in a limited number of tissues and human patients with FoxL2 deficiency display the Blepherophimosis-Ptosis- Epicanthus Inversus syndrome (BPES) associated with eyelid defects and premature ovarian failure in a sub- set of affected women. FoxL2 knockout mice exhibit a similar phenotype. FoxL2 is expressed in the pituitary of adult male and female mice and co-localizes with a-glycoprotein and FSH¿ subunits. FoxL2 protein is also readily detectable in gonadotrope-derived cell lines and siRNA-mediated knockdown strategies have demonstrated that FoxL2 is a critical mediator of activin actions on key transcriptional targets that have thus far been identified such as follistatin, FSH¿ and GnRH-R. By utilizing complimentary in vitro and in vivo models, the proposed studies of this application aim to provide a better understanding of the central role of FoxL2 in coordinating the Smad3-dependent activin program of gonadotropes, elucidate the mechanism underlying the partnership between FoxL2 and Smad3 and determine how FoxL2 function contributes to the local control of the activin/follistatin network of the pituitary, mechanisms that might prove to be relevant to other FoxL2-expressing tissues. Understanding the mechanism underlying FoxL2 action could illuminate strategies for the differential control of Smad3 targets and identify novel molecular targets with relevance to reproductive and other endocrine disorders.

描述（由适用提供）：本研究建议的目的是了解激活素对垂体性促性腺肿瘤主要靶标的细胞类型作用的机制的理解。激活素是多样性组织和细胞功能的多效调节剂，通常通过自分泌/旁分泌机制作用。它们在垂体中起着关键作用，以在局部调节促性腺瘤功能，并促进两个促性腺激素FSH和LH的差异表达和分泌。 Follistatins是分泌的糖蛋白，细胞外发挥作用，可通过反馈回路结合和调节TGF- - 家族的活化素和其他相关配体的局部生物利用度。在垂体中，与其他时候一样，激活素/follistatin网络的精确控制有助于维持靶细胞的功能完整性并防止病理的发展。激活素/卵泡素张力的动态控制是通过激活素和卵泡蛋白的相互作用以及激活素的自调节作用来实现的，从而对follistatin表达施加控制。遗传模型通过证明小鼠对卵泡素的无效表现出许多胚胎缺陷，并在出生后不久死亡，而卵泡过表达与不孕程度不同。在促性腺激素中，通过激活素介质SMAD3的协调作用和转录因子家族的成员FOXL2介导这种作用。功能性和生化实验表明，FOXL2是SMAD3的强制性伴侣，用于促性细胞衍生的细胞类型中Follistatin基因的激活素依赖性转录。 FOXL2在有限数量的组织中表达，而FOXL2缺乏症的人类患者显示出具有眼睑缺陷和与眼睑缺陷和早产卵巢衰竭相关的细胞症 - 症状 - epicanthus repicanthus invers综合征（BPE）。 FOXL2敲除小鼠表现出类似的表型。 FOXL2在成年雄性和雌性小鼠的垂体中表达，并与A-糖蛋白和FSH的亚基共定位。 FOXL2蛋白也很容易在促性腺细胞衍生的细胞系中检测到，而siRNA介导的敲低策略表明，FOXL2是迄今为止已鉴定出诸如Follistatin，fsh¿和GnRH-R之类的关键转录靶标的激活素作用的关键介体。 By utilizing complimentary in vitro and in vivo models, the proposed studies of this application aim to provide a better understanding of the central role of FoxL2 in coordination the Smad3-dependent activin program of gonadotropes, elucidate the mechanism underlying the partnership between FoxL2 and Smad3 and determine how FoxL2 function contributes to the local control of the activin/follistatin network of the pituitary, mechanisms that might被证明与其他表达FOXL2的组织有关。了解FOXL2作用的基础机制可以照亮SMAD3靶标的差异控制的策略，并确定与生殖和其他内分泌疾病相关的新型分子靶标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Local Control of the Pituitary by Activin Signaling and Modulation.

DOI：
10.2174/1876528901104010090
发表时间：
2011-01-01
期刊：
Open neuroendocrinology journal (Online)
影响因子：
0
作者：
Bilezikjian LM;Vale WW
通讯作者：
Vale WW

Cell-type specific modulation of pituitary cells by activin, inhibin and follistatin.

DOI：
10.1016/j.mce.2012.01.025
发表时间：
2012-08-15
期刊：
MOLECULAR AND CELLULAR ENDOCRINOLOGY
影响因子：
4.1
作者：
Bilezikjian, Louise M.;Justice, Nicholas J.;Blackler, Alissa N.;Wiater, Ezra;Vale, Wylie W.
通讯作者：
Vale, Wylie W.

Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium.