FSTL3: A Crucial Regulator of Sertoli Cell Proliferation

FSTL3：支持细胞增殖的关键调节因子

• 批准号: BB/N009886/1
• 负责人: Abir Mukherjee
• 金额: $ 53.25万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN009886%2F1
• 关键词: FSTL3; Crucial; Regulator; Sertoli; Cell

Notwithstanding current world population infertility in humans is on the rise. 1 in 10 couples is infertile and in about a third of the cases, the defect arises from the male. Testicular defects are among the principal causes of reproductive deficit in males. Perhaps due to environmental effects male infertility in animals is also on the rise. This has most likely contributed to the reduction in numbers of many animal species in the wild. Understanding mechanisms that regulate testicular development and function is therefore essential for development of therapeutic strategies to alleviate male infertility disorders.The two major functions of the testis are to produce testosterone and sperm throughout the reproductive life of the species. Generally this begins at puberty when testicular size increases. Increased testicular size is an indicator of active generation of sperm and testicular function. There is, however, a need for age-related waning of testis function so that mutations accumulated with age are not propagated in the population. For seasonal breeders an additional requirement is the cyclical increase and decrease of the testis with the beginning and end of each breeding season. Sertoli cells (SC) in the testis allow for the duplications and development of the cells that give rise to sperm and generally the total number of germ cells produced depends on the number of SC in a testis. This number is fixed very early in life and normally does not change with age.What is not clear is how the number of SC is determined and whether SC numbers in a testis can be increased later on in life. It is also unclear how testis size reduction is controlled in an age or season dependent manner. We have found that a natural cell product, follistatin-like 3 (FSTL3) might be crucial in regulating testicular development. Our findings in genetically modified mice lacking FSTL3 in all cells show increased testis size, and a lack of testis size reduction with age. Also, within the testis there is an increase in SC numbers and related increase in cells that give rise to sperm. We, therefore, hypothesise that testicular FSTL3 action is essential for limiting testicular size and age-related decline in testicular function. There are only two other mouse models with increased testis size, but neither of these have a block in age-dependent reduction of testicular size. Our FSTL3 deletion mouse model, therefore, allows us to ask several crucial questions regarding testis development and function. Here we will first determine whether SC multiplication can be increased by reducing FSTL3 in mice and in tissue culture cells. We will then investigate whether SC numbers, can be increased by deleting FSTL3 only in the SC. This will demonstrate whether SC numbers are controlled by local FSTL3 expressed in the SC or whether there is a systemic requirement for FSTL3 production. Furthermore, we will address whether removing FSTL3 after puberty increases SC numbers. This will demonstrate whether SCs can multiply beyond the first few days after birth, therefore providing the possibility of a therapeutic strategy of inducing SC growth and fertility in infertile males with limitingly small testes. Finally, we will identify which genes and cellular signalling pathways FSTL3 may influence to limit testicular size and help achieve reduction of testis size with age. Our research will, therefore, identify how FSTL3 regulates testis development and function and helps limit reproduction with age. We will be identify the molecular mechanisms of these actions, whether FSTL3 dependent SC number regulation is achieved through its expression solely in SC and whether SC can be induced to grow, by removing FSTL3 at any time after birth. The contributions from this work to our understanding of the processes underlying testis development may support development of preventative and therapeutic approaches to dealing more effectively with male infertility.

尽管目前的世界人口，人类不育症正在上升。每10对夫妇中就有1对是不育的，大约三分之一的情况下，缺陷来自男性。睾丸缺陷是男性生殖缺陷的主要原因之一。也许是由于环境的影响，动物雄性不育症也在增加。这很可能导致了许多野生动物物种数量的减少。因此，了解调节睾丸发育和功能的机制对于开发缓解男性不育症的治疗策略至关重要。睾丸的两个主要功能是在物种的整个生殖生命中产生睾酮和精子。一般来说，这开始于青春期，睾丸大小增加。睾丸大小增加是精子活跃生成和睾丸功能的指标。然而，需要与年龄相关的睾丸功能衰退，以便随着年龄的增长而积累的突变不会在人群中传播。对于季节性繁殖者来说，额外的要求是睾丸在每个繁殖季节的开始和结束时周期性地增加和减少。睾丸中的支持细胞（SC）允许产生精子的细胞的复制和发育，并且通常产生的生殖细胞的总数取决于睾丸中SC的数量。SC的数量在生命早期就已经确定，通常不会随着年龄的增长而变化，但目前尚不清楚SC的数量是如何确定的，以及睾丸中的SC数量是否会在生命后期增加。目前还不清楚睾丸大小的减少是如何以年龄或季节依赖的方式控制的。我们发现一种天然细胞产物卵泡抑素样3（FSTL 3）可能在调节睾丸发育中起关键作用。我们在所有细胞中缺乏FSTL 3的转基因小鼠中的研究结果显示睾丸大小增加，并且睾丸大小不会随着年龄的增长而减少。此外，在睾丸内，SC数量增加，产生精子的细胞也相应增加。因此，我们假设睾丸FSTL 3的作用对于限制睾丸大小和年龄相关的睾丸功能下降至关重要。只有另外两种小鼠模型睾丸大小增加，但这两种模型都没有阻止睾丸大小的年龄依赖性减少。因此，我们的FSTL 3缺失小鼠模型使我们能够提出关于睾丸发育和功能的几个关键问题。在这里，我们将首先确定是否可以通过减少小鼠和组织培养细胞中的FSTL 3来增加SC增殖。然后，我们将研究是否可以通过仅删除SC中的FSTL 3来增加SC编号。这将证明SC编号是否受SC中表达的本地FSTL 3控制，或者是否存在FSTL 3生产的系统要求。此外，我们将讨论青春期后去除FSTL 3是否会增加SC数量。这将证明SC是否可以在出生后的最初几天内繁殖，因此提供了在具有有限小睾丸的不育男性中诱导SC生长和生育力的治疗策略的可能性。最后，我们将确定哪些基因和细胞信号通路FSTL 3可能影响限制睾丸大小，并帮助实现睾丸大小随年龄的减少。因此，我们的研究将确定FSTL 3如何调节睾丸发育和功能，并帮助限制随着年龄的增长而繁殖。我们将确定这些作用的分子机制，FSTL 3依赖的SC数量调节是否仅通过其在SC中的表达实现，以及是否可以通过在出生后的任何时间去除FSTL 3来诱导SC生长。这项工作对我们理解睾丸发育过程的贡献可能有助于开发更有效地处理男性不育症的预防和治疗方法。

项目成果

A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities.

• DOI: 10.1242/dmm.047555
• 发表时间: 2021-02-19
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Vaughan D;Mitchell R;Kretz O;Chambers D;Lalowski M;Amthor H;Ritvos O;Pasternack A;Matsakas A;Vaiyapuri S;Huber TB;Denecke B;Mukherjee A;Widera D;Patel K
• 通讯作者: Patel K

Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention.

基于肌生长抑制素的肌肉生长促进干预措施导致杜氏肌营养不良小鼠模型的精子数量和质量减少。

• DOI: 10.4081/ejtm.2019.8904
• 发表时间: 2020
• 期刊: European journal of translational myology
• 影响因子: 2.2
• 作者: Vaughan D

Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development.

抑制激活素/肌肉生长抑制素信号传导会诱导骨骼肌肥大，但会损害小鼠睾丸发育。

• DOI: 10.4081/ejtm.2019.8737
• 发表时间: 2020
• 期刊: European journal of translational myology
• 影响因子: 2.2
• 作者: Vaughan D