Publications by authors named "Marie Maclennan"

6 Publications

  • Page 1 of 1

Tex19.1 inhibits the N-end rule pathway and maintains acetylated SMC3 cohesin and sister chromatid cohesion in oocytes.

J Cell Biol 2020 05;219(5)

Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.

Age-dependent oocyte aneuploidy, a major cause of Down syndrome, is associated with declining sister chromatid cohesion in postnatal oocytes. Here we show that cohesion in postnatal mouse oocytes is regulated by Tex19.1. We show Tex19.1-/- oocytes have defects maintaining chiasmata, missegregate their chromosomes during meiosis, and transmit aneuploidies to the next generation. Furthermore, we show that mouse Tex19.1 inhibits N-end rule protein degradation mediated by its interacting partner UBR2, and that Ubr2 itself has a previously undescribed role in negatively regulating the acetylated SMC3 subpopulation of cohesin in mitotic somatic cells. Lastly, we show that acetylated SMC3 is associated with meiotic chromosome axes in mouse oocytes, and that this population of cohesin is specifically depleted in the absence of Tex19.1. These findings indicate that Tex19.1 regulates UBR protein activity to maintain acetylated SMC3 and sister chromatid cohesion in postnatal oocytes and prevent aneuploidy from arising in the female germline.
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http://dx.doi.org/10.1083/jcb.201702123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199850PMC
May 2020

Mobilization of LINE-1 retrotransposons is restricted by in mouse embryonic stem cells.

Elife 2017 08 14;6. Epub 2017 Aug 14.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Mobilization of retrotransposons to new genomic locations is a significant driver of mammalian genome evolution, but these mutagenic events can also cause genetic disorders. In humans, retrotransposon mobilization is mediated primarily by proteins encoded by LINE-1 (L1) retrotransposons, which mobilize in pluripotent cells early in development. Here we show that TEX19.1, which is induced by developmentally programmed DNA hypomethylation, can directly interact with the L1-encoded protein L1-ORF1p, stimulate its polyubiquitylation and degradation, and restrict L1 mobilization. We also show that TEX19.1 likely acts, at least in part, through promoting the activity of the E3 ubiquitin ligase UBR2 towards L1-ORF1p. Moreover, loss of increases L1-ORF1p levels and L1 mobilization in pluripotent mouse embryonic stem cells, implying that prevents retrotransposition in the pluripotent phase of the germline cycle. These data show that post-translational regulation of L1 retrotransposons plays a key role in maintaining trans-generational genome stability in mammals.
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http://dx.doi.org/10.7554/eLife.26152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570191PMC
August 2017

Tex19.1 promotes Spo11-dependent meiotic recombination in mouse spermatocytes.

PLoS Genet 2017 Jul 14;13(7):e1006904. Epub 2017 Jul 14.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.

Meiosis relies on the SPO11 endonuclease to generate the recombinogenic DNA double strand breaks (DSBs) required for homologous chromosome synapsis and segregation. The number of meiotic DSBs needs to be sufficient to allow chromosomes to search for and find their homologs, but not excessive to the point of causing genome instability. Here we report that the mammal-specific gene Tex19.1 promotes Spo11-dependent recombination in mouse spermatocytes. We show that the chromosome asynapsis previously reported in Tex19.1-/- spermatocytes is preceded by reduced numbers of recombination foci in leptotene and zygotene. Tex19.1 is required for normal levels of early Spo11-dependent recombination foci during leptotene, but not for upstream events such as MEI4 foci formation or accumulation of H3K4me3 at recombination hotspots. Furthermore, we show that mice carrying mutations in Ubr2, which encodes an E3 ubiquitin ligase that interacts with TEX19.1, phenocopy the Tex19.1-/- recombination defects. These data suggest that Tex19.1 and Ubr2 are required for mouse spermatocytes to accumulate sufficient Spo11-dependent recombination to ensure that the homology search is consistently successful, and reveal a hitherto unknown genetic pathway promoting meiotic recombination in mammals.
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http://dx.doi.org/10.1371/journal.pgen.1006904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533463PMC
July 2017

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.

Cell Rep 2016 12;17(12):3269-3280

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. Electronic address:

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.
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http://dx.doi.org/10.1016/j.celrep.2016.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199341PMC
December 2016

Oocyte development, meiosis and aneuploidy.

Semin Cell Dev Biol 2015 Sep 8;45:68-76. Epub 2015 Oct 8.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. Electronic address:

Meiosis is one of the defining events in gametogenesis. Male and female germ cells both undergo one round of meiotic cell division during their development in order to reduce the ploidy of the gametes, and thereby maintain the ploidy of the species after fertilisation. However, there are some aspects of meiosis in the female germline, such as the prolonged arrest in dictyate, that appear to predispose oocytes to missegregate their chromosomes and transmit aneuploidies to the next generation. These maternally-derived aneuploidies are particularly problematic in humans where they are major contributors to miscarriage, age-related infertility, and the high incidence of Down's syndrome in human conceptions. This review will discuss how events that occur in foetal oocyte development and during the oocytes' prolonged dictyate arrest can influence meiotic chromosome segregation and the incidence of aneuploidy in adult oocytes.
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http://dx.doi.org/10.1016/j.semcdb.2015.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828587PMC
September 2015

Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline.

Cell Mol Life Sci 2014 May 18;71(9):1581-605. Epub 2013 Sep 18.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK,

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline.
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http://dx.doi.org/10.1007/s00018-013-1468-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983883PMC
May 2014