Biology subjects

Maciulyte, V.

Publications and source records attributed to Maciulyte, V..

3 recordsLinked to original sources

bioRxiv2024

Systematic identification of Y-chromosome gene functions in mouse spermatogenesis

The mammalian Y chromosome is essential for male fertility, but how individual Y genes regulate spermatogenesis is poorly understood. To resolve this question, we generate a deletion series of the mouse Y chromosome, creating thirteen Y-deletant mouse models and conducting exhaustive reproductive phenotyping. Eight Y genes, including several that are deeply conserved and exhibit testis-specific expression, are dispensable for spermatogenesis. For others, we uncover novel functions, including a role for Uty in establishment and differentiation of spermatogonia, and for Zfy2 in ensuring meiotic pairing and reciprocal recombination between the sex chromosomes. We also generate the first mouse equivalent of the human infertility AZFa deletion, revealing cumulative detrimental effects of Y-gene loss on spermatogenesis. We use single nuclei RNAseq to identify candidate mechanisms by which Y genes regulate the germ cell transcriptome and reveal an unexpected impact of Y genes on testis supporting cells. Our study represents a paradigm for the complete functional dissection of a mammalian Y chromosome and advances our knowledge of human infertility and Y-chromosome evolution.

genetics↗

bioRxiv2020

Generating single-sex litters: development of CRISPR-Cas9 genetic tools to produce all-male offspring

Animals are extremely useful genetic tools in science and global resources in agriculture. However, a single sex is often required in surplus, and current genetic methods for producing all-female or all-male litters are inefficient. Using the mouse as a model, we developed a synthetic, two-part bicomponent strategy for generating all-male litters. We achieved this using CRISPR-Cas9 genome editing technology to generate large stable knock-ins on the autosomes and X chromosome. The bicomponent system functions via the sex-specific co-inheritance of a Cas9 transgene and an sgRNA transgene targeting the essential Topoisomerase 1 gene. This technology proved to be highly efficient in generating on-target mutations, resulting in embryonic lethality of the target sex. Our study is the first to successfully generate all-male mammalian litters using a CRISPR-Cas9 bicomponent system and provides great strides towards generating single-sex litters for laboratory or agricultural research.

genetics↗

bioRxiv2017

ATR is a multifunctional regulator of male mouse meiosis

Meiotic cells undergo genetic exchange between homologous chromosomes through programmed DNA double-strand break (DSB) formation, recombination and synapsis1, 2. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes3-6. However, the meiotic functions of another major PIKK, ATR, have remained elusive, because germ line-specific depletion of this kinase is challenging. Using an efficient conditional strategy, we uncover roles for ATR in male mouse prophase I progression. Deletion of ATR causes chromosome axis fragmentation and germ cell elimination at mid pachynema. ATR is required for homologous synapsis, in a manner genetically dissociable from DSB formation. In addition, ATR regulates loading of recombinases RAD51 and DMC1 to DSBs and maintenance of recombination foci on synapsed and asynapsed chromosomes. Mid pachytene spermatocyte elimination in ATR deficient mice cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK-independent surveillance mechanism in the mammalian germ line. Our studies identify ATR as a multifunctional regulator of mouse meiosis.

cell biology↗