Carlos Egydio de Carvalho et al. (2007) International Worm Meeting "LAB-1 localizes to the AIR-2-free domain of prophase I diakinesis bivalents."

Monica Colaiacovo, Carlos Egydio de Carvalho

[International Worm Meeting, 2007]

Carlos Egydio de Carvalho et al. (2006) Development & Evolution Meeting "BLA-1, a New Meiotic Protein, Localizes to the AIR-2-free Domain of Prophase I Chromosomes"

Monica Colaiacovo, Carlos Egydio de Carvalho

[Development & Evolution Meeting, 2006]

In C. elegans, a single crossover recombination event at the terminal third of every chromosome pair, results in the formation of chiasmata, which underpinned by flanking sister chromatid cohesion, hold homologous chromosomes together. As a result, bivalents acquire a cruciform configuration in which homologs are displayed facing away from each other (long arms of the bivalent) and remain joined through their short arms. Proper chromosome segregation relies both on the prior formation of chiasmata during meiosis I and on the stepwise release of sister chromatid cohesion throughout metaphase I and II. The selective phosphorylation of the meiotic cohesin REC-8 by the Aurora kinase AIR-2 in the region distal to the chiasma (short arms), results in the separation of homologs while maintaining sister chromatids attached until the onset of anaphase II. The mechanisms involved in targeting AIR-2 specifically to the short arms of the bivalent and/or protecting REC-8 from AIR-2-mediated phosphorylation in the long arms remain obscure in C. elegans. Here we describe the initial characterization of a new meiotic protein, BLA-1 (Bivalent Long Arm), that localizes to the AIR-2-deprived arm of the bivalent during diakinesis. bla-1 mutants as well as bla-1 (RNAi) hermaphrodites have segregation defects as indicated by the presence of univalents in diakinesis accompanied by a high incidence of males and increased embryonic lethality among its progeny. An antibody raised against the C-terminus of BLA-1 shows that it associates along the full-length of chromosomes in late pachytene. During diplotene and diakinesis BLA-1 is localized between sister chromatids, a region that is protected from removal of cohesion in metaphase I. Analysis of BLA-1 localization in different meiotic mutants with disrupted assembly of the synaptonemal complex central core (syp-1, syp-2, syp-3), disrupted axis morphogenesis (rec-8,him-3), or with defects in initiation (spo-11), frequency/distribution (rec-1) or resolution of crossing-over events (msh-5), demonstrated that the chromosomal association of BLA-1 is dependent on the presence of intact axes morphogenesis but not of synapsis or recombination between homologs. Further work is currently underway to identify the role of BLA-1 in maintaining the stability of sister chromatid cohesion along the long arms of the bivalents.

Pilgrim, Dave et al. (2014) Evolutionary Biology of Caenorhabditis and Other Nematodes "THE SEX DETERMINING PATHWAY IN CAENORHABDITIS; TRA SUPPRESSORS AND FEM GENES"

Reidy, Keith, Pilgrim, Dave, Egydio de Carvalho, Carlos, Dewar, Jill

[Evolutionary Biology of Caenorhabditis and Other Nematodes, 2014]

Sex determination in Caenorhabditis is a rapidly evolving process that can provide insights into how biological pathways can be modified from a common set of ancestral genes. C. elegans and C. briggsae are two of three androdiocious species within the Elegans group. These two species are both morphologically and developmentally similar but their genetic control of hermaphroditism is different. XX animals in these species are somatically female but are capable of producing and storing sperm before switching to oocyte production. Previous work from our lab and Eric Haag's showed that the function of the Tra genes was similar between the two species, while mutations in C. briggsae fem-2 or fem-3 genes resulted in somatic but not germline feminization, suggesting that the sperm/oocyte switch must be controlled downstream of the Fem genes in C. briggsae XX animals. We have now extended that work, by isolating and characterizing suppressors of Cb-tra-2 and Cb-tra-3 ts mutations, in hope of identifying missense mutations which will help with the analysis of Fem protein function.Over 70 tra-2 suppressors were identified in the Pilgrim and Haag labs and several tra-3 suppressors in our lab by forward genetics (looking for the restoration of self-fertility to tra(ts) animals at the restrictive temperature). The results of these screens and the ongoing characterization will be presented. The majority of the tra-2 suppressors are alleles of the three fem genes, as expected, including a large set of mutations in Cb-fem-1, which had not been previously isolated by reverse genetics. A small set of interesting mutations complemented the fem genes and are phenotypically distinct from any other mutants described in C. elegans or C. briggsae. WGS has identified candidates for these suppressors and we are currently in the process of mapping the mutations to confirm that the lesion is responsible for their unique phenotypes, and the alleles are being separated from the tra-2 background to allow characterization of their phenotype.

Wuhr M et al. (2009) Cell "Size and speed go hand in hand in cytokinesis."

Wuhr M, Field CM, Mitchison TJ

[Cell, 2009]

In animal cells, cytokinesis is mediated by the constriction of a cortical ring. In this issue, Carvalho et al. (2009) show in embryos of the worm Caenorhabditis elegans that the rate of ring constriction during cytokinesis is proportional to the initial cell perimeter, ensuring that the duration of cytokinesis is cell-size independent.

Zarkower D et al. (1994) Worm Breeder's Gazette "mab-3 YAC Rescue"

De Bono M, Hodgkin JA, Zarkower D

[Worm Breeder's Gazette, 1994]

mab-3 YAC rescue David Zarkower, Mario de Bono, and Jonathan Hodgkin MRC Laboratory of Molecular Biology, Cambridge, England

Waddell, Brandon et al. (2021) International Worm Meeting "The C. elegans Shugoshin (SGO-1) is a cilia resident protein that interacts with TAC-1/TACC"

Li, Chunmei, Giesbrecht, Lesa, Timbers, Tiffany A., Park, Kwangjin, Waddell, Brandon, Quick, Evan, Egydio de Carvalho, Carlos, Leroux, Michel R.

[International Worm Meeting, 2021]

In organisms with monocentric chromosomes, the Shugoshin family of cell cycle regulators have conserved functions in spindle attachment and sister chromatid cohesion during mitosis and meiosis. In worms, the sole Shugoshin homolog (sgo-1) has early roles in meiosis but is otherwise dispensable for gamete and embryo viability. We have identified a novel function of SGO-1 in sensory neurons. sgo-1 is expressed in a series of adult amphid and phasmid neurons where the protein localizes to the base of cilia. sgo-1 mutants display behavioural and dauer entry defects consistent with dysfunctional cilia. These phenotypes are in turn rescued by a sgo-1(+) construct specifically expressed in cilia-producing neurons. In a screen for SGO-1-interacting proteins, we identified TAC-1, a regulator of spindle microtubule dynamics. TAC-1 co-localizes with SGO-1 in the base of cilia and a tac-1 mutation suppresses sgo-1 sensory and dauer entry defects. We are exploring the hypothesis that SGO-1 influences microtubule maintenance in the ciliary axoneme through the recruitment of TAC-1 to the basal body. These results add to a growing body of evidence suggesting that kinetochore and centrosomal proteins are transiently targeted to cilia and represent the first description of a non-nuclear role of Shugoshin in a post-differentiated cell type.

Eberhardt AG et al. (2008) Vet Parasitol "The Strongyloides (Nematoda) of sheep and the predominant Strongyloides of cattle form at least two different, genetically isolated populations."

Mayer WE, Eberhardt AG, Streit A, Bonfoh B

[Vet Parasitol, 2008]

Strongyloides sp. (Nematoda) are very wide spread small intestinal parasites of vertebrates that can form a facultative free-living generation. Most authors considered all Strongyloides of farm ruminants to belong to the same species, namely Strongyloides papillosus (Wedl, 1856). Here we show that, at least in southern Germany, the predominant Strongyloides found in cattle and the Strongyloides found in sheep belong to separate, genetically isolated populations. While we did find mixed infections in cattle, one form clearly dominated. This variety, in turn, was never found in sheep, indicating that the two forms have different host preferences. We also present molecular tools for distinguishing the two varieties, and an analysis of their phylogenetic relationship with the human parasite Strongyloides stercoralis and the major laboratory model species Strongyloides ratti. Based on our findings we propose that Strongyloides from sheep and the predominant Strongyloides from cattle should be considered separate species as it had already been proposed by [Brumpt, E., 1921. Recherches sur le determinisme des sexes et de l''evolution des Anguillules parasites (Strongyloides). Comptes rendu hebdomadaires des seances et memoires de la Societe de Biologie et de ses filiales 85, 149-152], but was largely ignored by later authors. For nomenclature, we follow [Brumpt, E., 1921. Recherches sur le determinisme des sexes et de l''evolution des Anguillules parasites (Strongyloides). Comptes rendu hebdomadaires des seances et memoires de la Societe de Biologie et de ses filiales 85, 149-152] and use the name S. papillosus for the Strongyloides of sheep and the name Strongyloides vituli for the predominant Strongyloides of cattle.

De Stasio E et al. (1994) Worm Breeder's Gazette "Mutagenesis of C. elegans Using N-ethyl-N-nitrosourea."

De Stasio E, Stanislaus D, Lephoto C

[Worm Breeder's Gazette, 1994]

Mutagenesis of C. elegans using N-ethyl-N-nitrosourea Elizabeth De Stasio, Dinesh Stanislaus and Catherine Lephoto. Department of Biology, Lawrence University, Appleton, Wl 54911

Sokolowski MB (2002) Nature "Neurobiology: social eating for stress."

Sokolowski MB

[Nature, 2002]

Behavioral ecologists have shown that many animals form social groups in conditions. Neurobiological evidence for this behaviour has now been discovered in the nematode worm, Caenorhabditis elegans. On pages 899 and 925 of this issue, de Bono et al. and Coates and de Bono present striking results on the genetic, molecular and neural mechanisms underlying nematode social feeding. These discoveries provide tantalizing insights into the effects of stress in social groupings.

Platzer K et al. (2018) Am J Hum Genet "De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies."

Stegmann APA, Bonati MT, Panis B, Smith-Hicks C, Lemke JR, Pepler A, Wilson C, Iascone M, McWalter K, Brasington C, Allen W, Di Donato N, Platzer K, Ramos L, Edwards SL, Jamra R, Gamble CN, Mandel H, Stobe P, Mahida S, Marquardt T, Demmer LA, Miller KG, Falik-Zaccai T, Pinz H, Hellenbroich Y, Sticht H, Kok F, Cho MT, Stumpel CTRM, Shinde DN, Angione KM

[Am J Hum Genet, 2018]

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.