Functional analysis of mammalian gametogenesis

Resumen

Gametogenesis is among the most complex and strictly regulated differentiation programme in which a diploid cell give rise to gametes making use of a unique reductional division. Our studies focuses on different macro molecular structures that operates during meiosis, such as the cohesin complex (STAG3), the synaptonemal complex (SIX6OS1), and the spermatoproteasome (PSMA8), which we have ultimately shown its essential role for mammalian fertility. Since a large fraction of human infertilities are asymptomatic and idiopathic, we and others have postulated that mutations in meiotic genes could be the molecular mechanism underlying this disease. One of the responsible for human infertility is the cohesin subunit STAG3. As we have shown in previous studies, women carrying an homozygous mutation in STAG3 gene presented premature ovarian failure (POF). The genetic depletion of STAG3 in mice leads to infertility in both sexes, phenocopying the human mutation. Recently, we have described how an anonymous gene variant in C14ORF39/SIX6OS1 that influences the recombination rate in humans is a new protein of the central element of the synaptonemal complex. By means of biochemical and genetic analyses we showed that SIX6OS1 interacts with the well-established protein synaptonemal complex central element 1 (SYCE1). Functionally, mice lacking SIX6OS1 were defective in chromosome synapsis at meiotic prophase I, which led to an arrest at the pachytene-like stage which in turns provokes non obstructive azoospermia. In accordance with its role as a modifier of the human recombination rate, SIX6OS1 is essential for the appropriate processing of intermediate recombination nodules before crossover formation. Our last work deepens in the role of the testis-specific proteasomal subunit α4s (PSMA8) during spermatogenesis, showing its localization in the central region of the synaptonemal complex. Mice deficient in PSMA8 are infertile, showing alterations in the proteostasis of several key meiotic players such as acetylated histones, SYCP1, SYCP3, CDK1 or TRIP13, which leads to an aberrant meiotic exit and finally to an early spermatid arrest.