Chen, Albert et al. (2015) International Worm Meeting "New longevity genes revealed by integrative analysis of daf-2 and glp-1 mutants."

Pande, Manjusha, Chen, Albert, McEachin, Richard, Hu, Patrick, Grant, Ana, Waters, Ian, Guo, Chunfang, Kruempel, Joseph

[International Worm Meeting, 2015]

FoxO transcription factors promote longevity across taxa. How they do so remains poorly understood. In C. elegans, the FoxO transcription factor DAF-16 extends life span in the contexts of reduced DAF-2 insulin-like signaling and germline ablation. To prioritize a subset of DAF-16/FoxO target genes for phenotypic analysis, we performed whole transcriptome profiling on two distinct daf-2 mutants and glp-1(e2141) mutants lacking a germline in the context of wild-type daf-16 and two daf-16 mutations that fully suppress life span extension. Integration of phenotypic data with transcriptome profiles defined a set of 46 DAF-16/FoxO target genes, the differential expression of which is associated with longevity (dal genes). daf-2 RNAi life span assays on loss-of-function mutants corresponding to nineteen dal genes revealed that mutation of five dal genes significantly reduces life span extension induced by daf-2 RNAi. One of these genes encodes an acetylcholinesterase homolog of unknown function. Our results underscore the efficacy of integrative analysis in defining tractable sets of DAF-16/FoxO target genes for detailed interrogation.

Chen, Albert et al. (2015) International Worm Meeting "New longevity genes revealed by integrative analysis of isoform-specific DAF-16/FoxO mutants."

McEachin, Richard, Yoshina, Sawako, Mitani, Shohei, Chen, Albert, Budaitis, Breane, Hu, Patrick, Guo, Chunfang, Hopkins, Christopher, Williams, Travis, Pande, Manjusha, Itani, Omar, Grant, Ana

[International Worm Meeting, 2015]

FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In C. elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. Mutant phenotypes and whole transcriptome profiling revealed a dominant role for DAF-16A over DAF-16F in both life span control and target gene regulation. Integration of these data sets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 target genes tested, three significantly influenced longevity, indicating that individual DAF-16/FoxO target genes can have disproportionately large effects on life span. Our approach provides a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions.

Chen, Albert et al. (2013) International Worm Meeting "Effects of C. elegans sgk-1 mutations on life span, stress resistance, and DAF-16/FoxO regulation."

Hu, Patrick, Guo, Chunfang, Ashrafi, Kaveh, Dumas, Kathleen, Chen, Albert

[International Worm Meeting, 2013]

The AGC family serine-threonine kinases Akt and Sgk are similar in primary amino acid sequence and substrate specificity in vitro, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, AKT-1 and SGK-1 are thought to act in concert to limit life span by phosphorylating and inhibiting the nuclear translocation of the FoxO transcription factor DAF-16. Here we show that AKT-1 and SGK-1 act in opposition to control C. elegans life span. In contrast to akt-1 null mutations, which prolong life in a daf-16/FoxO-dependent manner and confer stress resistance, sgk-1 null mutations shorten life span and enhance sensitivity to ultraviolet radiation and oxidative stress. Accordingly, an sgk-1 gain-of-function mutation increases life span in a DAF-16/FoxO-dependent manner. Therefore, SGK-1 promotes longevity. Intriguingly, although sgk-1 null mutants are short-lived, they are thermotolerant, suggesting that they are not short-lived due to general frailty secondary to developmental defects caused by lack of SGK-1 activity. Whereas AKT-1 inhibits DAF-16/FoxO target gene expression by promoting the sequestration of DAF-16/FoxO in the cytoplasm, SGK-1 does not significantly influence DAF-16/FoxO subcellular localization and does not regulate the expression of DAF- 16/FoxO target genes. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity through distinct mechanisms in vivo. Our findings highlight the need for re-evaluation of current paradigms of FoxO regulation by Sgk.

Chen, Albert et al. (2013) International Worm Meeting "daf-16/FoxO isoform-specific mutants reveal differential contributions to longevity in the contexts of reduced DAF-2 insulin-like signaling and germline ablation."

Hu, Patrick, Guo, Chunfang, Chen, Albert, Dumas, Kathleen, Mitani, Shohei, Williams, Travis, Yoshina, Sawako

[International Worm Meeting, 2013]

FoxO transcription factors promote longevity in invertebrates and may influence age-related disease in mammals. In C. elegans, the sole FoxO ortholog DAF-16 is required for lifespan extension in the contexts of reduced DAF-2 insulin-like signaling and germline ablation. The daf-16/FoxO locus encodes multiple protein isoforms that have distinct N-terminal amino acid sequences while sharing C-terminal sequences. Although the central role of DAF-16/FoxO in life span control by DAF-2 and the germline is well established, the relative contribution of distinct DAF-16/FoxO isoforms to longevity in these contexts is not known. Here, we characterize the first isoform-specific mutant alleles of daf-16/FoxO. Two independent daf-16a mutations and one daf-16f mutation fully suppress dauer arrest of Class 1 daf-2(e1368) animals, while partially suppressing dauer arrest of Class 2 daf-2(e1370) animals. Both daf-16a mutations partially suppress life span extension to the same extent in both daf-2 alleles. In contrast, daf-16f mutation fully suppresses life span extension in daf-2(e1368) but has no effect on daf-2(e1370) longevity. In glp-1(e2141) animals lacking a germline, both daf-16a mutations and the daf-16f mutation partially suppress longevity to the same extent. Our data suggests that DAF-16A plays a modest but consistent role in all three backgrounds, whereas DAF-16F contributes differentially to longevity in distinct contexts. Our work on multiple DAF-16/FoxO isoforms should inform research on aging in mammals, where multiple FoxO proteins modulate age-related disease phenotypes associated with Type 2 diabetes, cardiovascular disease, osteoporosis, and cancer.

Qi W et al. (2021) Nat Commun "Author Correction: The secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans."

Xu F, Pfeifer D, Baumeister R, Zhao Q, Long L, Qi W, Gromoff EDV, Yang W, Maier W

[Nat Commun, 2021]

Correction to: Nature Communications 10.1038/s41467-021-21516-6, published online 24 February 2021.The original version of this Article contained an error in the author affiliation.Ralf Baumeister was incorrectly associated with Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. He is associated with Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Germany Center for Biochemistry and Molecular Cell Research (Faculty of Medicine), Albert-Ludwigs-University Freiburg, Germany Signalling Research Centers BIOSS and CIBSS, Albert-Ludwigs-University Freiburg, Germany This has now been corrected in both the PDF and HTML versions of the Article.

Zhao C et al. (1993) Worm Breeder's Gazette "Cloning of the lin-32 Gene"

Emmons SW, Zhao C

[Worm Breeder's Gazette, 1993]

Cloning of the lin-32 gene Connie Zhao and Scott W. Emmons, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461

Hubbard EJA et al. (1994) Worm Breeder's Gazette "Genetic Analysis of sel-10."

Hubbard EJA, Greenwald IS

[Worm Breeder's Gazette, 1994]

Genetic analysis of sel-10 E. Jane Albert Hubbard and Iva Greenwald Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, New York, 10032

Emmons SW et al. (1994) Worm Breeder's Gazette "Strain Names for non-C. elegans Species."

Emmons SW, Fitch DHA, Leroi AM

[Worm Breeder's Gazette, 1994]

Strain names for non-C. elegans species Scott W. Emmonst, Armand Leroit, and David Fitch, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, Department of Biology, New York University, RmlOO9 Main Bldg., Washington Square, New York, NY 10003

Po MD et al. (2012) Neuron "Releasing the inner inhibition for axon regeneration."

Po MD, Calarco JA, Zhen M

[Neuron, 2012]

The adult mammalian central nervous system exhibits restricted regenerative potential. Chen etal. (2011) and El Bejjani and Hammarlund (2012) used Caenorhabditis elegans to uncover intrinsic factors that inhibit regeneration of axotomized mature neurons, opening avenues for potential therapeutics.

Hall DH et al. (1994) Worm Breeder's Gazette "Cytology of Degenerin-Induced Cell Death in the PVM Neuron"

Driscoll MA, Chalfie M, Gu GQ, Hall DH, Gong L

[Worm Breeder's Gazette, 1994]

Cytology of degenerin-induced cell death in the PVM neuron David H. Hall, Guoqiang Gu+, Lei Gong#, Monica Driscoll#, and Martin Chalfie+, * Dept. Neuroscience, Albert Einstein College of Medicine, Bronx, N.Y. 10461 + Dept. Biological Sciences, Columbia University, New York, N.Y. 10027 # Dept. Molecular Biology and Biochemistry, Rutgers University, Piscataway, N.J. 08855