Coordinating the Developmental and Cell Cycle Programs of Spermatogenesis

描述（由申请人提供）：为了避免细胞凋亡或癌变，多细胞生物中的细胞必须保持细胞周期和分化程序之间的紧密协调。这一挑战对于发育中的精母细胞来说尤其艰巨，因为精母细胞必须协调减数分裂染色体分离的复杂过程和多方面的发育程序，包括精子特异性结构的组装，染色质的重塑，从最初的静止状态到最终的全能状态，以及随后的细胞极性和运动的获得。在人类中，精子发生缺陷是男性不育的主要原因，而染色体分离、染色质重塑或中心体完整性方面的轻微缺陷与妊娠丢失和出生缺陷有关。该项目的长期目标是确定染色体分离的减数分裂程序如何与精子发生的发育（形态发生）程序协调，以及精子发生中的特定缺陷是否与可预测的胚胎后果有关。秀丽隐杆线虫众多的遗传、细胞学和分子特征使其成为研究这类问题的强大模型系统。最近的研究表明，许多精子发生基因在线虫和人类之间是保守的。这项建议的具体目的如下：1)利用细胞周期和细胞学标记分析具有多种减数分裂染色体分离缺陷的突变体，从而确定其分离缺陷的性质以及发育程序的各个子程序受到影响的程度；2)通过确定其动态亚细胞定位模式和识别其蛋白质结合伙伴来研究新的精子发生特异性基因spe-7的功能；3)探讨不同水平的中心体和染色体分离异常的精子是否产生具有明显和可预测缺陷的胚胎。这个项目非常适合本科生研究人员的参与，这些设备将有助于本系的研究基础设施。

DESCRIPTION (provided by applicant): To avoid apoptosis or cancerous transformations, cells within multi-cellular organisms must maintain a tight coordination between their cell cycle and differentiation programs. This challenge is particularly demanding for developing spermatocytes which must coordinate the complex process of meiotic chromosome segregation with a multi-faceted developmental program that includes the assembly of sperm-specific structures, the remodeling of chromatin into an initially quiescent yet ultimately totipotent state, and the subsequent acquisition of cell polarity and motility. In humans, defects in spermatogenesis are a major cause of male infertility, and minor defects in chromosome segregation, chromatin remodeling, or centrosome integrity are associated with pregnancy losses and birth defects. The long term goal of this project is to determine how the meiotic program of chromosome segregation is coordinated with the developmental (morphogenesis) program of spermatogenesis and whether specific defects in spermatogenesis are associated with predictable embryonic consequences. The numerous genetic, cytological, and molecular assets of the nematode C. elegans make it a powerful model system for investigating such questions and recent studies indicate that many spermatogenesis genes are conserved between worms and humans. The specific aims of this proposal are as follows: 1) Use a collection of cell cycle and cytological markers to analyze mutants with diverse defects in meiotic chromosome segregation and thus determine both the nature of their segregation defects and the extent to which various subprograms of the developmental program are affected, 2) Investigate the function of the novel spermatogenesis-specific gene, spe-7 by determining its dynamic sub-cellular localization pattern and identifying its protein binding partners, and 3) Explore whether sperm with different levels of centrosome and chromosome segregation abnormalities produce embryos with distinct and predictable defects. This project is well suited for involvement by undergraduate researchers, and the equipment will contribute to the research infrastructure of the department. PUBLIC HEALTH RELEVANCE: The proposed work is directly relevant to male infertility as it seeks to elucidate how the events of meiotic chromosome segregation are coordinated with the developmental events of spermatogenesis. It also seeks to establish C. elegans as a model system for addressing how defects in spermatogenesis contribute to pregnancy losses and birth defects. Lastly, the specific mutants selected for the purpose of analyzing meiotic chromosome segregation defects will also further our understanding of tau-tubulin kinase (a factor in the pathology of Alzheimer's), the role small RNAs in regulating gene expression, and a nematode-specific fertility protein which could potentially serve as a useful drug target against the various parasitic nematodes which infect more than one third of the world's population.