Biology subjects

Rathje, C. C.

Publications and source records attributed to Rathje, C. C..

5 recordsLinked to original sources

bioRxiv2022

The contribution of sex chromosome conflict to disrupted spermatogenesis in hybrid house mice

Incompatibilities on the sex chromosomes are important in the evolution of hybrid male sterility, but the evolutionary forces underlying this phenomenon are unclear. House mice (Mus musculus) lineages have provided powerful models for understanding the genetic basis of hybrid male sterility. X chromosome-autosome interactions cause strong incompatibilities in Mus musculus F1 hybrids, but variation in sterility phenotypes suggests a more complex genetic basis. Additionally, XY chromosome conflict has resulted in rapid expansions of ampliconic genes with dosage-dependent expression that is essential to spermatogenesis. Here we evaluated the contribution of XY lineage mismatch to male fertility and stage-specific gene expression in hybrid mice. We performed backcrosses between two house mouse subspecies to generate reciprocal Y-introgression strains and used these strains to test the effects of XY mismatch in hybrids. Our transcriptome analyses of sorted spermatid cells revealed widespread overexpression of the X chromosome in sterile F1 hybrids independent of Y chromosome subspecies origin. Thus, postmeiotic overexpression of the X chromosome in sterile F1 mouse hybrids is likely a downstream consequence of disrupted meiotic X-inactivation rather than XY gene copy number imbalance. Y-chromosome introgression did result in subfertility phenotypes and disrupted expression of several autosomal genes in mice with an otherwise nonhybrid genomic background, suggesting that Y-linked incompatibilities contribute to reproductive barriers, but likely not as a direct consequence of XY conflict. Collectively, these findings suggest that rapid sex chromosome gene family evolution driven by genomic conflict has not resulted in strong male reproductive barriers between these subspecies of house mice.

evolutionary biology↗

bioRxiv2019

Differential sperm motility mediates the sex ratio drive shaping mouse sex chromosome evolution

SummaryThe search for morphological or physiological differences between X- and Y-bearing mammalian sperm has provoked controversy for decades. Many potential differences have been proposed, but none validated, while accumulating understanding of syncytial sperm development has cast doubt on whether such differences are possible even in principle. We present the first ever mammalian experimental model to trace a direct link from a measurable physiological difference between X- and Y-bearing sperm to the resulting skewed sex ratio. We show that in mice with deletions on chromosome Yq, birth sex ratio distortion is due to a relatively greater motility of X-bearing sperm, and not to any aspect of sperm/egg interaction. Moreover, the morphological distortion caused by Yq deletion is more severe in Y-bearing sperm, providing a potential hydrodynamic basis for the altered motility. This reinforces a growing body of work indicating that sperm haploid selection is an important and underappreciated evolutionary force.

developmental biology↗

bioRxiv2019

A conserved requirement for Fbxo7 during male germ cell cytoplasmic remodelling

Summary statementFbxo7 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 haematopoietic phenotypes, Fbxo7-deficient male mice are completely 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 cells undergo cytoplasmic remodelling. 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-deficient males. Mutation of the Drosophila Fbxo7 orthologue, nutcracker (ntc) was previously shown to cause sterility at a similar stage of germ cell development, indicating that the requirement for Fbxo7 is conserved. The ntc phenotype was attributed to proteasome mis-regulation via an interaction with the proteasome regulator, DmPI31. Our data suggest rather that in mice, the requirement for Fbxo7 is either independent of its interaction with PI31, or relates specifically to cytoplasmic proteasome activity during spermiogenesis.

developmental biology↗

bioRxiv2018

Automated nuclear cartography reveals conserved sperm chromosome territory localization across 2 million years of mouse evolution

Measurements of nuclear organization in asymmetric nuclei in 2D images have traditionally been manual. This is exemplified by attempts to measure chromosome position in sperm samples, typically by dividing the nucleus into zones, and manually scoring which zone a FISH signal lies in. This is time consuming, limiting the number of nuclei that can be analyzed, and prone to subjectivity. We have developed a new approach for automated mapping of FISH signals in asymmetric nuclei, integrated into an existing image analysis tool for nuclear morphology. Automatic landmark detection defines equivalent structural regions in each nucleus, then dynamic warping of the FISH images to a common shape allows us to generate a composite of the signal within the entire cell population. Using this approach, we mapped the positions of the sex chromosomes and two autosomes in three mouse lineages (Mus musculus domesticus, Mus musculus musculus and Mus spretus). We found that in all three, chromosomes 11 and 19 tend to interact with each other, but are shielded from interactions with the sex chromosomes. This organization is conserved across 2 million years of mouse evolution.

genomics↗

bioRxiv2018

A high-throughput method for unbiased quantitation and categorisation of nuclear morphology

The physical arrangement of chromatin in the nucleus is cell type and species specific. This is particularly evident in sperm, in which most of the cytoplasm has been lost; the shape of the nucleus reflects the shape of the cell. Mice have distinctive falciform ( hook shaped) sperm heads and nuclei. Quantification of the differences in shape variation between mouse species and lines often relies on manual measurement and classification that leads to subjective results, making comparisons within and between samples difficult.\n\nWe have developed an analysis program for assessing the morphology of asymmetric nuclei, and characterised the sperm of mice from a range of inbred, outbred and wild-derived mouse lines. We find that laboratory lines have elevated sperm shape variability both within and between samples in comparison to wild-derived inbred lines, and that sperm shape in the F1 offspring of CBA and C57Bl6J lines is subtly affected by the direction of the cross.\n\nHierarchical clustering can distinguish distinct sperm shapes with greater efficiency and reproducibility than even experienced manual assessors. We quantified the range of morphological defects in the inbred BALB/c line, demonstrating we can identify different morphological subgroups. This approach has applications for studies of sperm development, infertility and toxicology.

genomics↗