A Conserved Requirement for Fbxo7 During Male Germ Cell Cytoplasmic Remodeling.

Fbxo7 is the substrate-recognition subunit of an SCF-type ubiquitin E3 ligase complex. It has physiologically important functions in regulating mitophagy, proteasome activity and the cell cycle in multiple cell types, like neurons, lymphocytes and erythrocytes. Here, we show that in addition to the previously known Parkinsonian and hematopoietic phenotypes, male mice with reduced Fbxo7 expression are sterile. In these males, despite successful meiosis, nuclear elongation and eviction of histones from chromatin, the developing spermatids are phagocytosed by Sertoli cells during late spermiogenesis, as the spermatids undergo cytoplasmic remodeling. Surprisingly, despite the loss of all germ cells, there was no evidence of the symplast formation and cell sloughing that is typically associated with spermatid death in other mouse sterility models, suggesting that novel cell death and/or cell disposal mechanisms may be engaged in Fbxo7 mutant males. Mutation of the Drosophila Fbxo7 ortholog, nutcracker (ntc) also leads to sterility with germ cell death during cytoplasmic remodeling, indicating that the requirement for Fbxo7 at this stage is conserved. The ntc phenotype was attributed to decreased levels of the proteasome regulator, DmPI31 and reduced proteasome activity. Consistent with the fly model, we observe a reduction in PI31 levels in mutant mice; however, there is no alteration in proteasome activity in whole mouse testes. Our results are consistent with findings that Fbxo7 regulates PI31 protein levels, and indicates that a defect at the late stages of spermiogenesis, possibly due to faulty spatial dynamics of proteasomes during cytoplasmic remodeling, may underlie the fertility phenotype in mice.

Nuclear morphologies: their diversity and functional relevance.

Studies of chromosome and genome biology often focus on condensed chromatin in the form of chromosomes and neglect the non-dividing cells. Even when interphase nuclei are considered, they are often then treated as interchangeable round objects. However, different cell types can have very different nuclear shapes, and these shapes have impacts on cellular function; indeed, many pathologies are linked with alterations to nuclear shape. In this review, we describe some of the nuclear morphologies beyond the spherical and ovoid. Many of the leukocytes of the immune system have lobed nuclei, which aid their flexibility and migration; smooth muscle cells have a spindle shaped nucleus, which must deform during muscle contractions; spermatozoa have highly condensed nuclei which adopt varied shapes, potentially associated with swimming efficiency. Nuclei are not passive passengers within the cell. There are clear effects of nuclear shape on the transcriptional activity of the cell. Recent work has shown that regulation of gene expression can be influenced by nuclear morphology, and that cells can drastically remodel their chromatin during differentiation. The link between the nucleoskeleton and the cytoskeleton at the nuclear envelope provides a mechanism for transmission of mechanical forces into the nucleus, directly affecting chromatin compaction and organisation.