Fundamental Mechanisms of Sperm Production: The Role of Microtubules

Abstract

Spermatogenesis is a feat of unparalleled biological scale and complexity. At any one time, the human testis harbours millions of germ cells in a continuous progression through multiple rounds of mitosis and meiosis, followed by a series of dramatic remodelling events. These processes are the critical determinant of sperm number, morphology, and motility, and 70% of infertile men have abnormalities in one, or more, of these parameters. Testament to its complexity, human spermatogenesis involves the expression of 84% of all protein-encoding genes and is touted as a health ‘canary in the coalmine’, as infertile men as a cohort, die younger than their fertile counterparts. Understanding the mechanisms of sperm production is thus essential, not only in the context of formulating infertility treatments, but also to identify additional health risks for the man and any potential offspring. In addition, sperm research has, and will continue to, shed light on gene function relevant to broad aspects of cell biology, as fertility is often the first, but not the only system, to fail, and may uncover strategies for contraceptive development. Microtubules (MTs) are a key driver of many aspects of sperm production. They form the fundamental machinery of mitosis and meiosis, sperm head shaping, and the sperm tail, in addition to playing roles in intracellular trafficking, including during acrosome biogenesis, and in germ-Sertoli cell adhesion. Through the use of mutant mouse models, our research has revealed the functional diversity of MTs in spermatogenesis is co-ordinated by a diverse suite of MT-associated proteins, including multiple MT-severing proteins from the katanin and spastin families, and the non-canonical tubulins, epsilon and delta. Moreover, we have shown that disruption of this MT regulatory toolbox has catastrophic consequences for sperm production and male fertility.