Ewbank JJ et al. (1998) Worm Breeder's Gazette "600 million years of Phox2."

Ewbank JJ, Brunet J-F, Pattyn A

[Worm Breeder's Gazette, 1998]

We are studying a C. elegans homologue of a couple of vertebrate neuron-specific transcription factors, to explore phylogenetic aspects of neuronal identity and of its transcriptional determination. Phox2a and Phox2b are two closely related homeodomain proteins of the paired-like family specifically expressed (mostly co-expressed) in specific classes of neurons in vertebrates (1,2). Careful analysis of their expression pattern has revealed a striking coherence which can be summarized by three overlapping neuroanatomical correlates: i) all noradrenergic neurons, ii) most central and peripheral neurons involved in the reflex circuits of the visceral nervous system, iii) cranial motoneurons. Published work and ongoing studies aim at reconstructing the transcriptional cascades in which Phox2a and Phox2b act and at defining which part of specific neuronal phenotypes they control (3,4). The sequencing of the C. elegans genome has unveiled a probable orthologue of Phox2a and b, D1007.1, which we call for the moment cePhox2. It is 88% identical to murine Phox2a in the homeodomain, a level of homology often associated with functional conservation among homeobox genes between vertebrates and invertebrates. We have cloned the cDNA by RT-PCR, thereby verifying the GeneFinder prediction. We have created transgenic lines harboring GFP under the control of the 1 kb upstream of CePhox2. The transgene is first expressed in early embryos. Expression continues at larval and adult stages in a few head and tail neurons, and, presumably ectopically, in the rostral and caudal part of the intestine. An antibody raised against the C-terminus of CePhox2 has confirmed its neuronal expression. Our current aim is to identify each Phox2 expressing neuron. We then plan to perform loss-of-fuction and gain-of-function studies. Our long-term hope, with the parallel mouse and worm studies, is to define what has changed and what has not throughout evolution in the "neuro-ontogenetic module" involving Phox2. Thanks to: Alan Coulson, Andy Fire and Theresa Stiernagle. (1) Tiveron et al. (1996) J. Neurosci., 16, 7649-7660. (2) Pattyn et al. (1997) Development, 124, 4065-4075. (3) Morin et al. (1997) Neuron, 18, 411-423. (4) Hirsch et al. (1998) Development, 125, 599-608.

Pujol N et al. (1999) Worm Breeder's Gazette "600 million years of Phox2 (II)"

Pujol N, Ewbank JJ, Brunet J-F

[Worm Breeder's Gazette, 1999]

We are studying a C. elegans homologue of a couple of vertebrate neuronal type-specific transcription factors of the prd-like homeobox gene superfamily, Phox2a and Phox2b (1,2,3). The predicted amino acid sequence of CePHOX2, also designated CEH-42 (4) and now renamed CEH-17 (5) is 88% identical to murine Phox2 proteins within the homeodomain, a level of similarity often associated with functional conservation between homeobox genes of vertebrates and invertebrates. Transgenic lines harboring gfp under the control of 1 kb of sequences upstream of CePhox2/ceh-17 reveal an expression largely restricted to a few neurons, mostly in the head. Among those, five are substantiated by immunohistochemistry with an antibody raised against the C-terminus of the predicted protein: ALA and 4 ventral neurons tentatively identified as SIB. Other neurons in the head, although they are also detected with a ceh-17/gfp fusion construct containing the two short introns of the gene are not detectable with the anti-CEH-17 antibody, raising the possibility that they correspond to ectopic expression sites. We have generated a library of about 350 000 genomes mutagenized with TMP/UV and isolated a target-selected mutation in CePhox2/ceh-17. The allele ceh-17(np1) corresponds to a 1.3 kb deletion extending from 0.6 kb upstram of the transcription start site to the first helix of the homeodomain and is thus expected to be a null. The homozygous mutants are viable. Crosses between the mutant strain and an integrated pceh-17/gfp strain allowed the detection of numerous axonal pathfinding defects. In particular, the posteriorly directed growth of the two ALA axons in the lateral cords is severely disrupted. Future work is aimed at better characterizing the role of CePhox2/ceh-17 in axonal navigation in these loss-of-function as well as in yet-to-be-generated gain-of-function mutants and assessing the orthology of ceh-17 and murine Phox2 by functional rescue. Thanks to: Remi Terranova and Gary Moulder. (1) Pattyn et al. (1997) Development, 124, 4065-4075, (2) Morin et al. (1997) Neuron, 18, 411-423 , (3) Ewbank et al. (1998) WBG 15 (3):17, (4) Hobert and Ruvkun (1998) ECWM98 (67), (5) Thomas Burglin, personal communication

N Pujol et al. (1999) International C. elegans Meeting "Axonal pathfinding defects in CePhox2/ceh-17 mutants"

JF Brunet, J Ewbank, N Pujol, R Terranova

[International C. elegans Meeting, 1999]

We are studying the C. elegans homologue of two vertebrate prd-like homeobox genes, Phox2a and Phox2b, involved in neuronal-subtype specification (1,2,3,4). The predicted amino acid sequence of CEH-17 is 88% identical to murine Phox2 proteins within the homeodomain, a level of similarity often associated with functional conservation between homeobox genes of vertebrates and invertebrates. An antibody raised against the C-terminus of CEH-17 reveals an expression restricted to 5 neurons located in the head ganglia: ALA and 4 ventral neurons tentatively identified as SMB. Interestingly, all those neurons send posteriorly directed axons along the lateral and sublateral cords. The expression is strongest from the 3-fold stage to L1 and decreases thereafter to a faint level in adults. In addition, different GFP fusions show a variable expression in other neurons not substantiated by immunohistochemistry and whose significance is therefore unclear. We have isolated a deletion allele in ceh-17 . The 1.3 kb deletion extends from 0.6 kb upstream of the transcription start site to the first helix of the homeodomain and is thus expected to create a null allele. Indeed, immunostaining of the mutant reveals no CEH-17 expression. The hermaphrodite and male homozygous mutants are viable and fertile. Crosses between the mutant strain and a strain in which GFP is expressed under the control of a unc-53 promoter (see abstract by Pujol and Bogaert) allowed ALA axonal pathfinding to be assessed in the mutant. In the wild type, the two ALA axons migrate on the lateral cords as far as the tail, beginning at the 3 fold stage until early L1 stage (i.e. a period corresponding to the strongest expression of CEH-17). In the ceh-17 mutant, the axons of 80% of the scored ALA neurons stop at the level of the vulva. In 5% of the cases, the axon stop at the vulva but then returns half way along the same lateral cord. Therefore, CePhox2/ceh-17 is required for the posteriorly directed growth of ALA axons in the second half of their trajectory, from the gonad to the tail. We are now ectopically expressing CEH-17 and assessing the functional conservation of CEH-17 and murine Phox2. (1) Morin et al. 97 Neuron 18 411-423 (2) Pattyn et al. Nature 99 in press (3) Ewbank et al. 98 WBG 15,3:17 (4) Pujol et al. 99 WBG 15,5:29

Pujol N et al. (2000) European Worm Meeting "The homeodomain protein CePHOX2/CEH-17 controls antero-posterior axonal growth in C. elegans"

Pujol N, Ewbank JJ, Torregrossa P, Brunet J-B

[European Worm Meeting, 2000]

The paired-like homeobox genes Phox2a and Phox2b are involved in neuronal subtype specification in the mouse (1,2). We characterised the Phox2 orthologue in C. elegans, called ceh-17. It encodes a protein with 88% identity in the homeodomain to murine Phox2a and Phox2b. Antibody staining and GFP constructs reveal CEH-17 expression in five head neurons, ALA and the 4 SIAs, which project axons towards the tail along the lateral and sublateral cords respectively. Expression starts at the late proliferative stage, and is strongest during axonal elongation from the coma to the three-fold stage. The function of these five neurons is still unknown, and their synaptic connectivity incompletely resolved. We have isolated a deletion allele in ceh-17 by PCR target-selected mutagenesis. Abrogation of ceh-17 function disrupts posterior axonal elongation of both ALA and SIA axons beyond the mid-body region. A fully penetrant stalling phenotype was observed for the ALA axons with more than 80% of them stopping within one body diameter of the gonad primordium. The phenotype in ALA was largely rescued by reintroduction of the wild-type ceh-17 gene or a chimeric construct in which the ceh-17 homeobox had been replaced by that of Phox2a, showing that ceh-17 is necessary for correct longitudinal outgrowth of ALA axon and further supporting the notion that Phox2a/b are the vertebrate orthologues of ceh-17. Conversely, ectopic expression of ceh-17 in the mechanoreceptors, using the mec-3 promoter, leads to exaggerated longitudinal axonal outgrowth. For example, the PLM axons, instead of stopping at the level of the ALM cell body, reached a position anterior to the AVM cell body in more than 20% of cases, and were occasionally more than twice their normal length, extending as far as the nerve ring. This ectopic outgrowth does not fasciculate with the sublateral ventral or the lateral cords, but pioneers its own extension. In the case of the AVM axon, most often its exaggerated anteriorward progress was stopped only when it reached the nose, whereupon it frequently turned back and grew posteriorly. Another phenotype is the growth of a posteriorly directed axon from the ALM cell body that could be seen in 24% of the cases as opposed to 2% in the wild type. Since some of the mechanoreceptors pioneer their track, these data show that ceh-17 is a novel gene involved in fasciculation-independent longitudinal axonal navigation. (1) Morin et al. 97, Neuron, 18, 411-423 (2) Pattyn et al. Nature 99, 399, 366-370.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.