Bargmann C (2024) Neuron "Cori Bargmann."

Bargmann C

[Neuron, 2024]

In an interview with Neuron, Cori Bargmann discusses C. elegans as a model organism, the importance of considering the animal's own world (thinking like a worm), choosing a scientific problem, and her experience as head of science at the Chan Zuckerberg Initiative and co-chair of the BRAIN Initiative.

Wu, Zheng et al. (2021) International Worm Meeting "Investigating non-apoptotic roles for egl-1"

Wu, Zheng, Pierce, Jonathan

[International Worm Meeting, 2021]

The Bcl-2 Homology (BH) 3-only protein EGL-1 is a key regulator of apoptosis pathway in Caenorhabditis elegans and is conserved across metazoans. Generally, decades of research have shown that expression of egl-1 is necessary and sufficient to trigger apoptosis in C. elegans. However, transcripts of BH3-only proteins are also detected in living neurons of healthy mammalian brains. Non-apoptotic roles and their underlying mechanisms for BH-3-only domain proteins are not well understood. Our lab discovered that egl-1 is expressed throughout the life of the worm in the URX pair of sensory neurons without inducing apoptosis. This expression depends cell autonomously on neuronal activity and calcium. URX is well known for its function as an oxygen sensor, but it also projects a process into the body cavity neuron where it senses signals from coelomic fluid. We are investigating non-apoptotic roles for egl-1 expression in URX. Our preliminary results show that both egl-1 mutation and URX-specific RNAi knock down of egl-1 impaired URX-related behaviors in worms. Further study of how egl-1 functions in URX without inducing apoptosis may reveal insight regarding the functions of BH-3-only domain proteins in the mammalian brain.

Guinnee MA et al. (2003) Parasitology "Host immune status affects maturation time in two nematode species--but not as predicted by a simple life-history model."

Viney ME, Read AF, Guinnee MA, Chan BH, Gemmill AW

[Parasitology, 2003]

In theory, the age at which maturation occurs in parasitic nematodes is inversely related to pre-maturational mortality rate, and cross-species data on mammalian nematodes are consistent with this prediction. Immunity is a major source of parasite mortality and parasites stand to gain sizeable fitness benefits through short-term adjustments of maturation time in response to variation in immune-mediated mortality. The effects of thymus-dependent immune responses on maturation in the nematode parasites Strongyloides ratti and Nippostrongylus brasiliensis were investigated using congenitally thymus-deficient (nude) rats. As compared with worms in normal rats, reproductive maturity of parasites (presence of eggs in utero) in nude rats occurred later in S. ratti but earlier in N. brasiliensis. Immune-mediated differences in maturation time were not associated with differences in worm length. Thymus-dependent immunity had no effect on prematurational mortality. Results are discussed in relation to theoretical expectations and possible explanations for the observed patterns in parasite maturation.

Deak P et al. (1980) Worm Breeder's Gazette "bal-X-1 chromosome."

Deak P, Fodor A

[Worm Breeder's Gazette, 1980]

The isolation and first characterization about a balancer chromosome temporarily called Bal-X-1 was presented at the Cold Spring Harbor meeting. This chromosome when heterozygous with an X chromosome marked by dpy-8 and unc-3 suppress crossover on this region. Characterizing the Bal-X-1 further on, we found, that Bal-X-1 viable only in heterozygous or hemizygous form. Bal-X-1 has been marked with lon-2(e678) allele. Bal-X-1 (lon) males are perfectly normal and fertile. Hermaphrodites heterozygous for Bal-X-1 always segregate males about 8-20% frequencies. The males are XO. Bal-X animals homozygous for her-1(e1520) (kindly provided by Jonathan Hodgin) are viable but almost completely sterile. Even if they lay some eggs, their oldest progeny has never been larger than L1, which die soon. Bal-X-1 can balance the following mutants: mn-110 (BH); let-2(e1470) (A.F.); let-15(e1471) (A.F.). We are going on to learn, whether Bal-X-1 is a translocation. In these experiments, we use stocks of double homozygous for two markers ( one in the medium and one in one of the ends the autosome) of the different autosomes and measure the recombination between them. If Bal-X-1 is a translocation like Dp-1 (BH) we expect, that the recombination frequency will be changed on the autosome being involved.

(2019) Development "The people behind the papers - Daniel Osorio, Elaine Chan, Joana Saramago and Ana Carvalho."

[Development, 2019]

Animal cytokinesis is driven by an actomyosin ring that assembles at the cell equator and constricts to physically separate the two daughters. Although myosin is known to be essential for cytokinesis in multiple systems, whether this requirement reflects its motor or actin crosslinking activities has recently been a matter of contention. A new paper in Development now addresses this problem using the first divisions of the <i>Caenorhabditis elegans</i> embryo as a model. We caught up with the paper's three first authors Daniel Osorio, Elaine Chan and Joana Saramago, and their supervisor Ana Carvalho, Principal Investigator at the University of Porto's i3S consortium, to find out more about the story.

Lama D et al. (2010) Biochemistry "Identification of core structural residues in the sequentially diverse and structurally homologous Bcl-2 family of proteins."

Lama D, Sankararamakrishnan R

[Biochemistry, 2010]

The Bcl-2 family of proteins regulates the intrinsic pathway of apoptosis and plays a significant role in mitochondrial outer membrane permeabilization. Bcl-2 homologues belonging to both anti- and pro-apoptotic classes have been identified in diverse organisms. While anti-apoptotic Bcl-2 proteins possess up to four BH sequence domains (BH1-BH4), the pro-apoptotic counterparts have either three BH (BH1-BH3) domains or only the BH3 domain. Many anti-apoptotic viral homologues do not seem to have any detectable BH homology regions and exhibit a very low level of sequence identity with other Bcl-2 family members. However, structures determined for several Bcl-2 anti- and pro-apoptotic proteins and their viral homologues show a remarkably conserved helical fold characterized by a central hydrophobic helix surrounded by five or six amphipathic helices. In this study, we have analyzed 16 nonredundant Bcl-2 structures from human, mouse, Caenorhabditis elegans, and five different viral species. While the length of the central hydrophobic helix is preserved in all the Bcl-2 structures, variations in length are observed for other helices. We performed multiple-structure alignment of all 16 structures. Eighty structurally equivalent positions, the bulk of them in the helical regions, constituted the ungapped blocks in the structure-based sequence alignment. Analysis of helix bundle geometry indicates that helix-helix packing differed in different Bcl-2 structures. This is presumably to accommodate disparate residue substitutions. Residue properties such as solvent accessibility, conservation of chemical nature, and/or size and involvement in interhelical interactions were analyzed in each position of the ungapped alignment regions. A sequence motif made up of small amino acids has been detected in the central helix that is proposed to be important for helix-helix association. We have found that residues in 22 positions in the helical regions are buried, exhibit conservation in hydrophobicity and/or size, and participate in interhelical interactions in at least 12 of the 16 structures studied. We also found 15 additional positions in which residues exhibit two of the three properties investigated. We suggest that these positions constitute the important structural core in the diverse Bcl-2 family members and could play a significant role in the folding of the protein. Results of our studies have been used in the identification of three putative Bcl-2 homologues from three different viral organisms. This study will help in the genome-wide identification of hitherto unrecognized Bcl-2 family members, especially in viral genomes.

Strasser A et al. (2018) Cell Death Differ "Viewing BCL2 and cell death control from an evolutionary perspective."

Vaux DL, Strasser A

[Cell Death Differ, 2018]

The last 30 years of studying BCL2 have brought cell death research into the molecular era, and revealed its relevance to human pathophysiology. Most, if not all metazoans use an evolutionarily conserved process for cellular self destruction that is controlled and implemented by proteins related to BCL2. We propose the anti-apoptotic BCL2-like and pro-apoptotic BH3-only members of the family arose through duplication and modification of genes for the pro-apoptotic multi-BH domain family members, such as BAX and BAK1. In that way, a cell suicide process that initially evolved as a mechanism for defense against intracellular parasites was then also used in multicellular organisms for morphogenesis and to maintain the correct number of cells in adults by balancing cell production by mitosis.

Cirillo, L. et al. (2015) International Worm Meeting "Coordinating Cdk1 and Plk1 activation for mitotic entry in early C. elegans embryos and human cells."

Pindard, L., Thomas, Y., Martino, L., Santamaria, A., Gotta, M., Schwager, F., Van Hove, L., Panbianco, C., Cirillo, L.

[International Worm Meeting, 2015]

Entry into mitosis is regulated by several kinases including Cdk1, Aurora A and Plk1. However, how the activity of these kinases is coordinated in space and time is not fully understood. Our laboratories have recently shown that SPAT-1, an activator of Plk1, is phosphorylated by Cdk-1 at several sites in C. elegans. Our in vivo and in vitro data revealed that phosphorylation of the N-terminal sites is crucial to promote the interaction with PLK-1 and its activation. Together, our results suggest the existence of a positive feedback loop that connects CDK-1 and PLK-1 via SPAT-1 and ensures a robust control of cell division timing during embryonic development.The human ortholog of SPAT-1, Bora, regulates several aspects of mitosis (Bruinsma et al. 2014, Chan et al 2008, Macurek et al. 2008, Seki et al. 2008). Although phosphorylation of Bora is not strictly required to activate Plk1 (Seki et al. 2008, our unpublished data) we find that Cdk1 phosphorylation of Bora greatly increases Plk1 activation in vitro. We have mapped the Cdk1 phosphorylation sites of Bora. Based on the results obtained in C. elegans, we have mutated a number of N-terminal sites and found that Bora ability to activate Plk1 is greatly reduced in vitro. We are currently testing the function of these sites in human cells by monitoring these mutants in vivo. Our data will help to shed light on the activation mechanisms of Plk1 by Bora. Since Plk1 is overexpressed in many cancers, understanding the precise mechanisms of activation of this kinase will help the design of anti-cancer drugs.References:Bruinsma W. et al. J Cell Sci. 2014; Chan EH. et al. Chromosoma. 2008; Macurek L. et al. Nature. 2008; Seki A. et al. Science. 2008.

Saleel Raut et al. (2008) C.elegans Neuronal Development Meeting "HLH-3, a C. elegans Achaete/Scute protein, has a role in the axonal pathfinding of hermaphrodite-specific motor neuron (HSN) that is independent of UNC-40."

Aixa Alfonso, Saleel Raut

[C.elegans Neuronal Development Meeting, 2008]

The basic helix loop helix protein, HLH-3, is a member of the achaete/scute family in C. elegans hlh-3 mutants have an egg-laying defective (Egl) phenotype. We have shown (Doonan et al., 2008 submitted) that the mutant phenotype results from abnormal axonal pathfinding in hermaphrodite-specific motor neurons (HSNs) that fail to innervate the vulval muscles. The NETRIN/UNC-6 receptor UNC-40/DCC is necessary for the guidance of the HSN axons (Garriga et al.,1993; Chan et al., 1996; Gitai et al., 2003; Adler et al., 2006). We hypothesized that mutant animals are not uncoordinated (Unc). Currently we are looking at SYG-1, a receptor on HSN''s that binds with the guidepost signal SYG-2 for proper synapse formation (Shen et al., 2004), as a possible target of HLH-3.

Erin Peden et al. (2005) International Worm Meeting "Identification of additional pro-apoptotic BH3 only proteins in C. elegans."

Ding Xue, David Breckenridge, Erin Peden

[International Worm Meeting, 2005]

The Bcl-2 family of proteins is a group of conserved cell death regulators, first defined by the human proto-oncogene bcl-2, which promotes cell survival and was identified by virtue of its overexpression in a number of B-cell lymphomas. They are characterized by the presence of at least one of four conserved Bcl-2 homology (BH) domains and are found in organisms as distantly related as C. elegans and humans. Interestingly, members of this family can be either anti-apoptotic or pro-apoptotic and can form heterodimers with selected family members. The pro-apoptotic family members include proteins with multiple BH domains such as Bax and Bak and proteins with a single BH3 motif, which are named BH3-only proteins. BH3-only Bcl-2 proteins have been found to play important roles in activating the apoptotic program. However, due to the low overall sequence conservation and small region of homology (about 9 amino acids), BH3-only proteins are difficult to identify. In C. elegans, two BH3-only proteins, EGL-1 and CED-13, have been found and there are likely additional BH3-only proteins involved in regulating programmed cell death in nematodes. Current bioinformatics tools are not designed to identify short sequence motifs in the large sequence databases. A simple BLAST search for the consensus BH3 domain does not yield the known BH3 containing proteins. In order to identify BH3 containing proteins in silico, we have developed a BH3 search algorithm, which correctly identifies known BH3-containing proteins in C. elegans along with promising candidate genes. We are in the process of determining the potential roles of these candidate genes in C. elegans apoptosis using the RNAi approach or available deletion mutations in candidate genes. Our BH3 search algorithm may provide a promising tool to identify unknown BH3 only proteins that may affect apoptosis in C. elegans and in other organisms such as Drosophila where BH3-only proteins have yet to be found.