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1. The tardigrade Hypsibius exemplaris dramatically upregulates DNA repair pathway genes in response to ionizing radiation

   https://doi.org/10.1016/j.cub.2024.03.019  

   Clark-Hachtel, Courtney M.; Hibshman, Jonathan D.; De Buysscher, Tristan; Stair, Evan R.; Hicks, Leslie M.; Goldstein, Bob (May 2024, Current Biology)

   Tardigrades can survive remarkable doses of ionizing radiation, up to about 1,000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigrade Hypsibius exemplaris suffers DNA damage upon gamma irradiation, but the damage is repaired. We show that this species has a specific and robust response to ionizing radiation: irradiation induces a rapid upregulation of many DNA repair genes. This upregulation is unexpectedly extreme—making some DNA repair transcripts among the most abundant transcripts in the animal. By expressing tardigrade genes in bacteria, we validate that increased expression of some repair genes can suffice to increase radiation tolerance. We show that at least one such gene is important in vivo for tardigrade radiation tolerance. We hypothesize that the tardigrades’ ability to sense ionizing radiation and massively upregulate specific DNA repair pathway genes may represent an evolved solution for maintaining DNA integrity. 

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2. Modified meiosis in the tardigrade Hypsibius exemplaris maintains heterozygosity across the genome

   https://doi.org/10.1093/genetics/iyag167  

   Coke, Adriana N; Zhang, Siqin Aurora; Papell, Lillian D; Burch, Christina L; Goldstein, Bob (July 2026, GENETICS)

   Lenormand, T (Ed.)

   Abstract In asexual reproduction, meiosis must be bypassed or altered to maintain ploidy from mother to daughter without fertilization. Most of the ways meiosis can be modified to this end are expected to reduce heterozygosity within individuals; however, many asexual species are highly heterozygous. Asexual reproduction is especially common among species of microscopic, desiccation-tolerant animals such as rotifers, nematodes, and tardigrades, but the cellular and genetic mechanisms underlying asexual reproduction have not been definitively documented in any species of tardigrade. Here, we show that the asexual tardigrade Hypsibius exemplaris fails to complete the cell division of meiosis I, followed by a complete meiosis II-like division, and reproduction proceeds without detectable loss of heterozygosity. We used a combined cytological and genomic approach to characterize the mechanism of reproduction and pattern of allele inheritance in this species. Furthermore, we identified heterozygous variants in a subset of transcriptionally active genes consistent with loss of function in one allele, suggesting that maintained heterozygosity in this species allowed divergence between alleles over time. This work establishes the meiotic mechanism and inheritance pattern of reproduction in H. exemplaris, which provides a framework for interpreting genetic variation in this organism as a laboratory model. Additionally, our finding that meiosis is modified in H. exemplaris via a mechanism that maintains heterozygosity across the genome adds to a growing list of asexual animals that have evolved to reproduce clonally despite the expected long-term costs. 

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3. Extensive loss of Wnt genes in Tardigrada

   https://doi.org/10.1186/s12862-021-01954-y  

   Chavarria, Raul A.; Game, Mandy; Arbelaez, Briana; Ramnarine, Chloe; Snow, Zachary K.; Smith, Frank W. (December 2021, BMC Ecology and Evolution)

   Abstract Background Wnt genes code for ligands that activate signaling pathways during development in Metazoa. Through the canonical Wnt (cWnt) signaling pathway, these genes regulate important processes in bilaterian development, such as establishing the anteroposterior axis and posterior growth. In Arthropoda, Wnt ligands also regulate segment polarity, and outgrowth and patterning of developing appendages. Arthropods are part of a lineage called Panarthropoda that includes Onychophora and Tardigrada. Previous studies revealed potential roles of Wnt genes in regulating posterior growth, segment polarity, and growth and patterning of legs in Onychophora. Unlike most other panarthropods, tardigrades lack posterior growth, but retain segmentation and appendages. Here, we investigated Wnt genes in tardigrades to gain insight into potential roles that these genes play during development of the highly compact and miniaturized tardigrade body plan. Results We analyzed published genomes for two representatives of Tardigrada, Hypsibius exemplaris and Ramazzottius varieornatus . We identified single orthologs of Wnt4 , Wnt5 , Wnt9 , Wnt11 , and WntA , as well as two Wnt16 paralogs in both tardigrade genomes. We only found a Wnt2 ortholog in H. exemplaris . We could not identify orthologs of Wnt1 , Wnt6 , Wnt7 , Wnt8 , or Wnt10 . We identified most other components of cWnt signaling in both tardigrade genomes. However, we were unable to identify an ortholog of arrow / Lrp5/6 , a gene that codes for a Frizzled co-receptor of Wnt ligands. Additionally, we found that some other animals that have lost several Wnt genes and are secondarily miniaturized, like tardigrades, are also missing an ortholog of arrow / Lrp5/6 . We analyzed the embryonic expression patterns of Wnt genes in H. exemplaris during developmental stages that span the establishment of the AP axis through segmentation and leg development. We detected expression of all Wnt genes in H. exemplaris besides one of the Wnt16 paralogs. During embryo elongation, expression of several Wnt genes was restricted to the posterior pole or a region between the anterior and posterior poles. Wnt genes were expressed in distinct patterns during segmentation and development of legs in H. exemplaris , rather than in broadly overlapping patterns. Conclusions Our results indicate that Wnt signaling has been highly modified in Tardigrada. While most components of cWnt signaling are conserved in tardigrades, we conclude that tardigrades have lost Wnt1 , Wnt6 , Wnt7 , Wnt8 , and Wnt10 , along with arrow / Lrp5/6 . Our expression data may indicate a conserved role of Wnt genes in specifying posterior identities during establishment of the AP axis. However, the loss of several Wnt genes and the distinct expression patterns of Wnt genes during segmentation and leg development may indicate that combinatorial interactions among Wnt genes are less important during tardigrade development compared to many other animals. Based on our results, and comparisons to previous studies, we speculate that the loss of several Wnt genes in Tardigrada may be related to a reduced number of cells and simplified development that accompanied miniaturization and anatomical simplification in this lineage. 

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4. Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle

   https://doi.org/10.1083/jcb.201811100  

   Xia, Yuntao; Pfeifer, Charlotte R.; Zhu, Kuangzheng; Irianto, Jerome; Liu, Dazhen; Pannell, Kalia; Chen, Emily J.; Dooling, Lawrence J.; Tobin, Michael P.; Wang, Mai; et al (August 2019, The Journal of Cell Biology)

   Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation. 

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5. Constricted migration increases DNA damage and independently represses cell cycle

   Pfeifer, C. (May 2018, Molecular biology of the cell)

   Cell migration through dense tissues or small capillaries can elongate the nucleus and even damage it, and any impact on cell cycle has the potential to affect various processes including carcinogenesis. Here, nuclear rupture and DNA damage increase with constricted migration in different phases of cell cycle-which we show is partially repressed. We study several cancer lines that are contact inhibited or not and that exhibit diverse frequencies of nuclear lamina rupture after migration through small pores. DNA repair factors invariably mislocalize after migration, and an excess of DNA damage is evident as pan-nucleoplasmic foci of phosphoactivated ATM and gamma H2AX. Foci counts are suppressed in late cell cycle as expected of mitotic checkpoints, and migration of contact-inhibited cells through large pores into sparse microenvironments leads also as expected to cell-cycle reentry and no effect on a basal level of damage foci. Constricting pores delay such reentry while excess foci occur independent of cell-cycle phase. Knockdown of repair factors increases DNA damage independent of cell cycle, consistent with effects of constricted migration. Because such migration causes DNA damage and impedes proliferation, it illustrates a cancer cell fate choice of "go or grow." 

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