Germ cell-specific LINC complexes and their relevance for nuclear remodelling, shaping and fertility

• Applicant: Professor Dr. Manfred Alsheimer
• Subject Area: Cell Biology ; Reproductive Medicine, Urology
• Term: from 2012 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226311706

Infertility is an increasing problem in our society and applies to approximately 15% of the couples that aim to have children. A frequent cause of male infertility is the inability to form functional regularly shaped sperm heads. In most cases the ultimate reason for the underlying pathological defects is unclear. Recent studies, however, indicate that LINC complexes could play a critical role in this context. LINC complexes are nuclear envelope bridging complexes that mediate a direct connection of nuclear structures with the cytoskeleton. They were found to be pivotal for nuclear migration, positioning and anchoring and for meiotic chromosome movements. In previous studies we could demonstrate that postmeiotic cells form unique LINC complexes showing a conspicuous behavior that closely correlates with the shaping process. This in turn suggests that they have a vital role in sperm head formation and nuclear elongation. Direct evidence for such a role came from our recent study where we could demonstrate that Sun4 deficiency provokes the generation of severely defective and entirely misshaped spermatids. The aim of the current project is now to further enlighten our still fragmentary knowledge about the actual composition, interaction and function of LINC complexes in spermatids. In light of this, we within a first subproject would like to dig deeper into the specific properties of Sun4. We in particular will address its topological and biochemical characteristics and its specific role within Sun4 dependent LINC complexes. A second subproject will be directed to the actual function of Sun5, which we intend to approach with immunohistochemical and biochemical methods and in particular also by means of a Sun5 knock out mouse model. Another subproject deals with the specific function of Sun1 during spermiogenesis. To this end we will generate a transgenic mouse line that will allow us to analyze in depth Sun1 function and behavior during sperm differentiation in vivo. Finally, we would like to make use of wildtype as well as Sun4 and Sun5 deficient spermatids, respectively, to survey the hypothesized role of LINC complexes in membrane spacing.

• DFG Programme: Research Grants