Publications by authors named "Katherine Kretovich Billmyre"

6 Publications

  • Page 1 of 1

Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility.

Nat Commun 2021 03 3;12(1):1420. Epub 2021 Mar 3.

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.

In several species, Piwi/piRNA genome silencing defects cause immediate sterility that correlates with transposon expression and transposon-induced genomic instability. In C. elegans, mutations in the Piwi-related gene (prg-1) and other piRNA deficient mutants cause a transgenerational decline in fertility over a period of several generations. Here we show that the sterility of late generation piRNA mutants correlates poorly with increases in DNA damage signaling. Instead, sterile individuals consistently exhibit altered perinuclear germ granules. We show that disruption of germ granules does not activate transposon expression but induces multiple phenotypes found in sterile prg-1 pathway mutants. Furthermore, loss of the germ granule component pgl-1 enhances prg-1 mutant infertility. Environmental restoration of germ granule function for sterile pgl-1 mutants restores their fertility. We propose that Piwi mutant sterility is a reproductive arrest phenotype that is characterized by perturbed germ granule structure and is phenocopied by germ granule dysfunction, independent of genomic instability.
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http://dx.doi.org/10.1038/s41467-021-21635-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930041PMC
March 2021

Genetic background impacts the timing of synaptonemal complex breakdown in Drosophila melanogaster.

Chromosoma 2020 12 17;129(3-4):243-254. Epub 2020 Oct 17.

Stowers Institute for Medical Research, Kansas City, MO, 64110, USA.

Experiments performed in different genetic backgrounds occasionally exhibit failure in experimental reproducibility. This is a serious issue in Drosophila where there are no standard control stocks. Here, we illustrate the importance of controlling genetic background by showing that the timing of a major meiotic event, the breakdown of the synaptonemal complex (SC), varies in different genetic backgrounds. We assessed SC breakdown in three different control stocks and found that in one control stock, y w; sv, the SC broke down earlier than in Oregon-R and w stocks. We further examined SC breakdown in these three control backgrounds with flies heterozygous for a null mutation in c(3)G, which encodes a key structural component of the SC. Flies heterozygous for c(3)G displayed differences in the timing of SC breakdown in different control backgrounds, providing evidence of a sensitizing effect of this mutation. These observations suggest that SC maintenance is associated with the dosage of c(3)G in some backgrounds. Lastly, chromosome segregation was not affected by premature SC breakdown in mid-prophase, consistent with previous findings that chromosome segregation is not dependent on full-length SC in mid-prophase. Thus, genetic background is an important variable to consider with respect to SC behavior during Drosophila meiosis.
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http://dx.doi.org/10.1007/s00412-020-00742-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666587PMC
December 2020

chromosome and autosomal recombination are differentially sensitive to disruptions in SC maintenance.

Proc Natl Acad Sci U S A 2019 10 30;116(43):21641-21650. Epub 2019 Sep 30.

Stowers Institute for Medical Research, Kansas City, MO 64110;

The synaptonemal complex (SC) is a conserved meiotic structure that regulates the repair of double-strand breaks (DSBs) into crossovers or gene conversions. The removal of any central-region SC component, such as the transverse filament protein C(3)G, causes a complete loss of SC structure and crossovers. To better understand the role of the SC in meiosis, we used CRISPR/Cas9 to construct 3 in-frame deletions within the predicted coiled-coil region of the C(3)G protein. Since these 3 deletion mutations disrupt SC maintenance at different times during pachytene and exhibit distinct defects in key meiotic processes, they allow us to define the stages of pachytene when the SC is necessary for homolog pairing and recombination during pachytene. Our studies demonstrate that the chromosome and the autosomes display substantially different defects in pairing and recombination when SC structure is disrupted, suggesting that the chromosome is potentially regulated differently from the autosomes.
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http://dx.doi.org/10.1073/pnas.1910840116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815145PMC
October 2019

The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing.

PLoS Genet 2019 03 28;15(3):e1008004. Epub 2019 Mar 28.

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote germ cell immortality, and we identified a separation-of-function allele of C. elegans gsp-2 that is compromised for germ cell immortality and is also defective for small RNA-induced genome silencing and meiotic but not mitotic chromosome segregation. Previous work has shown that GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. At the generation of sterility, gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents, histone methylation and histone phosphorylation defects in oocytes, phenotypes that mirror those observed in sterile small RNA-mediated genome silencing mutants. Our data suggest that a meiosis-specific function of GSP-2 ties small RNA-mediated silencing of the epigenome to germ cell immortality. We also show that transgenerational epigenomic silencing at hemizygous genetic elements requires the GSP-2 phosphatase, suggesting a functional link to small RNAs. Given that LAB-1 localizes to the interface between homologous chromosomes during pachytene, we hypothesize that small localized discontinuities at this interface could promote genomic silencing in a manner that depends on small RNAs and the GSP-2 phosphatase.
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http://dx.doi.org/10.1371/journal.pgen.1008004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456222PMC
March 2019

Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation.

Dev Dyn 2015 Apr 13;244(4):564-76. Epub 2015 Mar 13.

Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.

Background: Morphogenesis of vertebrate craniofacial skeletal elements is dependent on a key cell population, the cranial neural crest cells (NCC). Cranial NCC are formed dorsally in the cranial neural tube and migrate ventrally to form craniofacial skeletal elements as well as other tissues. Multiple extracellular signaling pathways regulate the migration, survival, proliferation, and differentiation of NCC.

Results: In this study, we demonstrate that Shh expression in the oral ectoderm and pharyngeal endoderm is essential for mandibular development. We show that a loss of Shh in these domains results in increased mesenchymal cell death in pharyngeal arch 1 (PA1) after NCC migration. This increased cell death can be rescued in utero by pharmacological inhibition of p53. Furthermore, we show that epithelial SHH is necessary for the early differentiation of mandibular cartilage condensations and, therefore, the subsequent development of Meckel's cartilage, around which the dentary bone forms. Nonetheless, a rescue of the cell death phenotype does not rescue the defect in cartilage condensation formation.

Conclusions: Our results show that SHH produced by the PA1 epithelium is necessary for the survival of post-migratory NCC, and suggests a key role in the subsequent differentiation of chondrocytes to form Meckel's cartilage.
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http://dx.doi.org/10.1002/dvdy.24256DOI Listing
April 2015

One shall become two: Separation of the esophagus and trachea from the common foregut tube.

Dev Dyn 2015 Mar 2;244(3):277-88. Epub 2014 Dec 2.

Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.

The alimentary and respiratory organ systems arise from a common endodermal origin, the anterior foregut tube. Formation of the esophagus from the dorsal region and the trachea from the ventral region of the foregut primordium occurs by means of a poorly understood compartmentalization process. Disruption of this process can result in severe birth defects, such as esophageal atresia and tracheo-esphageal fistula (EA/TEF), in which the lumina of the trachea and esophagus remain connected. Here we summarize the signaling networks known to be necessary for regulating dorsoventral patterning within the common foregut tube and cellular behaviors that may occur during normal foregut compartmentalization. We propose that dorsoventral patterning serves to establish a lateral region of the foregut tube that is capable of undergoing specialized cellular rearrangements, culminating in compartmentalization. We review established as well as new rodent models that may be useful in addressing this hypothesis. Finally, we discuss new experimental models that could help elucidate the mechanism behind foregut compartmentalization. An integrated approach to future foregut morphogenesis research will allow for a better understanding of this complex process.
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http://dx.doi.org/10.1002/dvdy.24219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778253PMC
March 2015