Regulation of Stem Spermatogonia in the Mature Testis

成熟睾丸中精原细胞干的调节

• 批准号: 9039479
• 负责人: WILLIAM Wallace WRIGHT
• 金额: $ 39.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-20 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039479
• 关键词: Address; Adult; Affect; Affinity; Amino Acids; Bathing; Binding Sites; Biological Process; Biopsy; Cells; Collaborations; Complement; Data; Employee Strikes; Equilibrium; Evaluation; Fertility; Foundations; GDNF receptors; Germ Cells; Growth; Human; Individual; Infertility; Instruction; Intrinsic factor; Kinetics; Knowledge; Maintenance; Mammals; Modeling; Mus; Mutation; Oligospermia; Organ; Phosphotransferases; Physiological; Play; Process; Production; Protein Tyrosine Kinase; Regulation; Role; Signal Transduction; Spermatogenesis; Spermatogonia; Staging; Stem cells; Testing; Testis; Transcript; Translating; Undifferentiated; adult stem cell; glial cell-line derived neurotrophic factor; hormone therapy; in vivo; inhibitor/antagonist; mRNA Expression; male; man; men; mouse model; protein expression; response; restoration; self-renewal; sertoli cell; sperm cell; spermatogenic epithelium structure; stem; stem cell differentiation

PROJECT SUMMARY (See instructions): An essential requirement for sustaining male fertility is maintaining an adequate number of stem spermatogonia, the foundation of spennatogenesis. To achieve this, when the stem cells divide, some progeny must remain stem spermatogonia while other progeny differentiate. It is obvious that the correct balance between self-renewing replication and differentiation of stem spermatogonia is crucial to male fertility, and there is indirect evidence that GDNF plays an important role in maintaining this balance in the normal mature testis. However, we known almost nothing about the in vivo regulation of this balance in the mature organ, of the specific function of GDNF in the adult testis, or if physiological changes in GDNF expression significantly affect the replication or differentiation of the stem cells. To address these critical issues, we have developed a unique mouse model that allows GDNF signaling to the stem spermatogonia to be specifically and reversibly inhibited in vivo by an ATP antagonist. Using this model, we have generated the first direct evidence that GDNF is required for maintaining the stem spermatogonial pool in a normal mature testis. Additionally, we have shown that when inhibition of GDNF signaling is reversed, the stem cells begin to rebuild the stem cell pool. Importantly, our data demonstrate that some stem spermatogonia are lost when GDNF signaling is inhibited for as little as 2 days, while other stem cells survive for up to 11 days. This suggests that factors intrinsic or extrinsic to the stem cells modulate the response to GDNF. Using this new mouse model we propose in Specific Aim 1 to define the mechanisms'responsible for the loss of stem spermatogonia upon inhibition of GDNF signaling and to detenmine why some cells are lost rapidly while others more slowly. Building on these results, we also propose to collaborate with Project 1 to determine if GDNF mRNA expression and/or stem spermatogonial numbers are significantly reduced in some oligospermic men. Specific Aim 2 studies the capacity of stem spermatogonia to repopulate the testis once their numbers are partially depleted. In doing so, we will identify the extent to which a defined number of stem spermatogonia can restore this pool and the biological processes responsible for this restoration. Additionally, in collaboration with Project 1 we will study oligospermic men who are receiving endocrine therapy to increase} sperm production in order to determine if in men who have a positive response to therapy, there is bath an increase in GDNF expression and/or an increase in numbers of stem spermatogonia. To jour knowledge, these specific aims constitute the first detailed in vivo analysis of theresponse of stem sjaermatogonia or any other adult stem cell to the inhibition and then restoration of signaling by an essbntial growth factor. We anticipate that the results from these studies will make an important contribution to the evaluation and eventually the treatment of infertile men.

项目摘要（请参阅说明）： 维持男性生育能力的基本要求是维持足够数量的茎原理，这是脊髓式生成的基础。为了实现这一目标，当干细胞分裂时，一些后代必须保持干精子性精子，而其他后代则分化。很明显，自我更新复制与茎精子分化之间的正确平衡对于男性生育至关重要，并且有间接的证据表明，GDNF在维持正常成熟睾丸的平衡方面起着重要作用。但是，我们几乎对成熟器官中这种平衡的体内调节，GDNF在成人睾丸中的特定功能或GDNF表达中的生理变化显着影响干细胞的复制或分化显着影响。为了解决这些关键问题，我们开发了一个独特的鼠标模型，该模型允许GDNF发出向STEM精子的信号 由ATP拮抗剂专门和可逆地抑制体内。使用此模型，我们已经生成了第一个直接证据，表明在正常成熟的睾丸中维持茎精子池需要GDNF。此外，我们已经表明，当抑制GDNF信号传导时，干细胞开始重建干细胞池。重要的是，我们的数据表明，当GDNF信号传导抑制短短2天时，而其他干细胞存活长达11天时，某些茎精子会丢失。这表明对干细胞的固有或外在的因素调节对GDNF的反应。使用这种新的小鼠模型，我们建议在特定目标1中提出，以定义抑制GDNF信号传导后的茎精子造成的机制，并确定为什么某些细胞损失迅速而其他细胞较慢而其他细胞则更慢。在这些结果的基础上，我们还建议与项目1合作，以确定是否是否 在某些寡头男性中，GDNF mRNA表达和/或茎的精子数量显着降低。特定目标2研究了茎精子的能力，一旦睾丸的数量部分耗尽了睾丸。通过这样做，我们将确定定义数量的STEM精子数量可以恢复该池的程度以及负责这种恢复的生物学过程。 此外，我们将与项目1合作研究正在接受内分泌疗法以增加精子产生的寡头男性，以确定在对治疗有积极反应的男性中是否会增加GDNF表达和/或STEM精子数量的增加。据《杂志》，这些特定目的构成了对茎sjaermatogonia或任何其他成年干细胞的体内响应的第一个详细介绍，以抑制，然后通过essbntial生长因子恢复信号传导。我们预计这些研究的结果将为评估和最终对不育男性的治疗做出重要贡献。

项目成果

The Regulation of Spermatogonial Stem Cells in an Adult Testis by Glial Cell Line-Derived Neurotrophic Factor.

• DOI: 10.3389/fendo.2022.896390
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Wright, William W.

Spermatogonial Stem Cell Numbers Are Reduced by Transient Inhibition of GDNF Signaling but Restored by Self-Renewing Replication when Signaling Resumes.

• DOI: 10.1016/j.stemcr.2021.01.015
• 发表时间: 2021-03-09
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Parker N;Laychur A;Sukwani M;Orwig KE;Oatley JM;Zhang C;Rutaganira FU;Shokat K;Wright WW
• 通讯作者: Wright WW