Mechanisms of male germ cell development: Centriole regulation, sperm tail formation, and membrane fluidity

Abstract

Male infertility affects ~7 % of men and arises from a complex interplay of genetic, physiological, and environmental factors. This thesis explores novel gene functions crucial for spermatogenesis, offering insights into the molecular basis of male fertility. The number and position of centrioles are strictly regulated in mitotic cells, however, centriole dynamics during male meiosis remain largely unexplored. Beyond their role in genetic segregation, centrioles in male germ cells transform into basal bodies forming sperm flagellum. The first study identifies MEICEN as a novel testis-specific regulator of centriole dynamics and sperm tail formation. MEICEN is a centriolar satellite protein, that controls CETN1 and 2 (Centrin1 and 2) distribution between centrioles and centriolar satellites, ensuring centriole stability and integrity during remodeling. Meicen knockout (KO) mice exhibit supernumerary centrioles, leading to disorganized sperm tails, and ultimately male infertility. These findings establish MEICEN as a meiosis-specific regulator of centriole width and number in spermatogenesis, shedding light on the intricate mechanisms governing male germ cell development. Impaired sperm motility presents a substantial challenge in reproductive medicine contributing to male infertility cases. The second study identifies coiled-coil domain containing protein 28 A (CCDC28A), a germ cell upregulated protein, as essential for sperm tail movement. Knockout models reveal that CCDC28A deficiency disrupts the head-tail coupling apparatus (HTCA), causing sperm tail defects and reduced motility. Transmission electron microscopy reveals disruptions at the capitulum-basal plate junction of the HTCA in CCDC28A mutants, resulting in head bending within the neck region, often accompanied by midpiece thickening. These findings establish CCDC28A as a critical factor in male fertility, contributing to sperm tail morphogenesis through HTCA formation. Membrane composition is vital for male germ cell development. The third study identifies AdipoR2 as a key regulator of the meiosis-specific lipidome. AdipoR2 upregulates the expression of the fatty acid elongase ELOVL2, both transcriptionally and post-transcriptionally, facilitating synthesis of very long chain polyunsaturated fatty acids (VLC-PUFA). AdipoR2 knockout testes show VLC-PUFA depletion, palmitic acid accumulation, resulting in cellular membrane stiffening and nuclear envelope invagination. This condition disrupts the nuclear peripheral distribution of meiotic telomeres, leading to errors in homologous synapsis and recombination. Additionally, the stiffened membrane impairs intercellular bridge formation and the germ cell syncytium, disrupting the orderly arrangement of cell types within the seminiferous tubules. These findings highlight the AdipoR2-ELOVL2 pathway’s crucial role in maintaining membrane fluidity for proper chromosome dynamics during meiosis.