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

Wilhelm, Thomas et al. (2015) International Worm Meeting "A C.elegans RNAi screen identifies novel genes with antagonistic pleiotropic effects."

Medina, Rebeca, Wilhelm, Thomas, Richly, Holger, Byrne, Jonathan

[International Worm Meeting, 2015]

In 1957, George C. Williams published the antagonistic pleiotropy hypothesis of aging, which was later mathematically supported by Brian Charlesworth. This theory predicts that some genes mediate beneficial effects early in life when natural selection is strong, but are detrimental late in life when natural selection is weak. Natural selection favors these beneficial effects on fitness early in life at the expense of enriching harmful effects late in life; hence leading to the evolution of aging.We screened 800 chromatin regulators and transcription factors in order to identify novel genes that exhibit antagonistic pleiotropy. Genes were inactivated in the post-reproductive phase by the use of RNAi from day nine of adulthood onwards. The screen led to the identification of several genes that significantly extend lifespan upon late-life inactivation, while shortening lifespan when inactivated early in life.The forkhead box (FOX) A transcription factor pha-4 represents a top candidate of our screen. Late-life inactivation of pha-4 resulted in a strong lifespan extension of 33%. In contrast, inactivation of pha-4 from the first day of adulthood reduced C.elegans lifespan. This is of particular interest, as pha-4 has been shown to mediate diet-restriction and germline-less induced longevity. Our findings indicate that, depending on the age, pha-4 is either needed for normal lifespan and longevity or exhibits detrimental effects. We are currently aiming to identify and to characterize the biological processes underlying the observed negative effects of pha-4 late in life.Generally, genes that behave according to the antagonistic pleiotropy hypothesis may represent promising drug targets to fight age-associated diseases. Our findings emphasize that timing needs to be addressed to fully understand how genes and gene networks impinge on the aging process.

Hodgkin JA et al. (1997) Worm Breeder's Gazette "CGC Genetic Map and Nomenclature Subcontract"

Hodgkin JA, Durbin RM, Martinelli SD

[Worm Breeder's Gazette, 1997]

1997 Genetic Map The deadline for new genetic map data to be incorporated into the 1997 Genetic Map of Caenorhabditis elegans (Printed Version) is 30 April 1997. Data can be sent: (preferably) by e-mail to: cgc@mrc-lmb.cam.ac.uk. Forms for data submission are available by e-mail or fax, on request to this address. (or alternatively) by fax or mail, to: Jonathan Hodgkin, MRC-LMB, Hills Road, Cambridge CB2 2QH, England [fax (+44) 1223 412142]

Lakhina, Vanisha et al. (2015) International Worm Meeting "Identification of a new regulator of age-dependent axon regeneration by characterizing the neuronal IIS/FOXO transcriptome from isolated adult C. elegans neurons."

Murphy, Coleen, Ashraf, Jasmine, Arey, Rachel, Lakhina, Vanisha, Williams, April, Kaletsky, Rachel, Landis, Jessica

[International Worm Meeting, 2015]

The ability of axons to regenerate depends on the age of the neuron in all model organisms tested, including humans. Young axons (including CNS axons) regenerate efficiently, whereas old axons either do not regrow at all, or make errors while navigating to their target (Verdu et al., 2000; Wu et al., 2007). Insulin/IGF-1 signaling (IIS) is a critical regulator of the most important biological decisions, from rates of growth, development, and metabolism, to reproduction and longevity. Long-lived daf-2 insulin/IGF1 receptor mutants exhibit enhanced axonal regenerative capacity in older GABAergic motor neurons and PLM mechanosensory neurons (Byrne et al., 2014, Lakhina et al., submitted). This occurs through the activity of the DAF-16/FOXO transcription factor, which regulates regeneration independent of lifespan, and in a neuron-specific manner (Byrne et al., 2014). While the global, whole-worm targets of DAF-16 were identified in C. elegans using whole-worm transcriptional analyses more than a decade ago (Murphy et al., 2003; Lee et al., 2003; McElwee et al., 2003), neuron-specific DAF-16 targets remain elusive. We have selectively isolated adult C. elegans neurons and performed transcriptional profiling. The neuron-enriched set includes synaptic machinery, channels, neurotransmitters, and signaling components, as well as >700 previously uncharacterized genes. Comparison of the embryonic and larval neuronal transcriptomes with this new adult neuronal transcriptome revealed a shift in functional categories from developmental processes to neuronal function and behavior. We next used this approach to directly identify IIS/FOXO targets from isolated daf-2 and daf-16;daf-2 neurons. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets. We also selectively sequenced six mechanosensory neurons and identified 63 mechanosensory neuron-specific DAF-16 targets. We discovered that a transcription factor that is upregulated in daf-2 neurons is almost entirely responsible for daf-2's enhanced ability to regenerate PLM mechanosensory axons with age. These studies identify a set of adult neuronal FOXO targets and potentially a new set of candidate age-dependent axonal regeneration factors.

Herman RK et al. (1997) Worm Breeder's Gazette "STATUS OF THE CAENORHABDITIS GENETICS CENTER (CGC)"

Herman RK, Stiernagle TL

[Worm Breeder's Gazette, 1997]

May 31, 1997 will mark the end of our current five-year contract with the NIH National Center for Research Resources, which supports the activities of the CGC. The activities in St. Paul have involved primarily the acquisition, maintenance and distribution of stocks and information about stocks, acquisition and maintenance of the C. elegans bibliography, and publication and distribution of The Worm Breeder's Gazette (WBG) and WBG Subscriber Directory. Genetic nomenclature and the genetic map have been managed for the period 1992-1997 by Jonathan Hodgkin (CGC Map Curator) on a subcontract. Currently, the subcontract provides half of Sylvia Martinelli's salary, plus travel and minor expenses. Additional support from within the MRC Laboratory of Molecular Biology and the Sanger Centre has been used to fund other essential resources such as computer equipment, as well as Jonathan's and Richard Durbin's time. Richard has been involved in mapkeeping through his work on ACeDB. We are pleased that Jonathan, Richard and Sylvia agreed to continue their work for another five years. We have submitted an application for a new five year contract that would include a subcontract for nomenclature and mapkeeping on essentially the same terms as before. A description of the nomenclature and mapkeeping activities is given in the following abstract. We are grateful to Leon Avery for setting up our CGC gopher server and also for arranging for the electronic submission of WBG abstracts (as well as abstracts for various C. elegans meetings). His C. elegans WWW server has become an essential resource for the worm community. We were therefore pleased to include Leon (only 5% effort) in a second subcontract as part of our new CGC application. We welcome comments and suggestions about any of the CGC activities.

Hodgkin J (2004) Curr Biol "Jonathan Hodgkin."

Hodgkin J

[Curr Biol, 2004]

Jonathan Hodgkin graduated from Oxford in 1971 and then did a PhD with Sydney Brenner at MRC LMB in Cambridge, studying behavioural genetics in the nematode Caenorhabditis elegans. Later, after a couple of years working with myxobacteria as a postdoc in Dale Kaiser''s lab at Stanford, he returned to LMB as a staff member, where he remained for most of the subsequent two decades. In the year 2000, he moved to Oxford as Professor of Genetics in the Department of Biochemistry, switching his major research interests from developmental genetics and sex determination to the study of host-pathogen interactions in the worm. For the past ten years, he has acted as curator of the C. elegans genetic map and gene nomenclature, and he is currently President of the Genetics Society of Great Britain.

Soltesz, Z. et al. (2011) International Worm Meeting "Carbon dioxide avoidance is mediated by a diverse set of sensory neurons in C. elegans."

Soltesz, Z., de Bono, M., Bretscher, A. J.

[International Worm Meeting, 2011]

Monitoring carbon dioxide levels has a twofold importance for many living organisms: CO2 can act as a sensory cue for food or other animals, while regulating internal CO2 levels is an important part of homeostasis. C. elegans relies on diffusion for gas exchange, and avoids CO2 levels as low as 1%. We are interested in the neural and molecular mechanisms underlying the C. elegans CO2 avoidance behaviour. Mutants defective in the tax-4 or tax-2 genes, which encode the a and b subunits, respectively, of a cGMP-gated ion channel, showed reduced CO2 avoidance in behavioural assays1,2. By expressing tax-2 cDNA from neuron-specific promoters in tax-2 mutants to rescue the avoidance behaviour, and by imaging neurons using the genetically encoded calcium indicator YC3.60, we have shown that sensory neurons previously implicated in oxygen, temperature, and salt-sensing, including BAG, AFD and ASE, are CO2 sensors as well3. We have observed both persistent and transient cell-intrinsic calcium-responses in several sensory neurons, suggesting that CO2 stimuli could modulate neural activity in C. elegans in a complex manner. We are therefore investigating how CO2 stimuli can affect neural processing in downstream neurons. 1 Andrew Jonathan Bretscher, Karl Emanuel Busch, and Mario de Bono, A carbon dioxide avoidance behavior is integrated with responses to ambient oxygen and food in Caenorhabditis elegans. PNAS 105(23):8044-8049 2 Elissa A. Hallem and Paul W. Sternberg, Acute carbon dioxide avoidance in Caenorhabditis elegans. PNAS 105(23):8038-8043 3 Andrew Jonathan Bretscher, Eiji Kodama-Namba, Karl Emanuel Busch, Robin Joseph Murphy, Zoltan Soltesz, Patrick Laurent and Mario de Bono, Temperature, Oxygen, and Salt-Sensing Neurons in C. elegans Are Carbon Dioxide Sensors that Control Avoidance Behavior. Neuron 69(6):1099-1113.

Hodgkin J (2017) Genetics "Frontiers of Knowledge: An Interview with 2017 Edward Novitski Prize Recipient Jonathan Hodgkin."

Hodgkin J

[Genetics, 2017]

The Genetics Society of America's Edward Novitski Prize recognizes a single experimental accomplishment or a body of work in which an exceptional level of creativity and intellectual ingenuity has been used to design and execute scientific experiments to solve a difficult problem in genetics. The 2017 winner, Jonathan Hodgkin, used elegant genetic studies to unravel the sex determination pathway in Caenorhabditis elegans He inferred the order of genes in the pathway and their modes of regulation using epistasis analyses-a powerful tool that was quickly adopted by other researchers. He expanded the number and use of informational suppressor mutants in C. elegans that are able to act on many genes. He also introduced the use of collections of wild C. elegans to study naturally occurring genetic variation, paving the way for SNP mapping and QTL analysis, as well as studies of hybrid incompatibilities between worm species. His current work focuses on nematode-bacterial interactions and innate immunity.

Edgley ML et al. (1995) International C. elegans Meeting "CYBERWORMS"

Collins D, Bryer J, Baillie DL, Edgley ML, Rose AM

[International C. elegans Meeting, 1995]

We are engaged in two projects to improve the alignment of the genetic and physical maps for C. elegans. The Genetic Toolkit project uses PCR to tie the endpoints of balanced deficiencies to the physical map; and the CGAT project uses microinjection of cloned cosmids from the worm sequencing project to generate transgenic arrays that are used to rescue mapped, balanced lethal mutations. Both projects are generating large amounts of genetic map information, which is being integrated into the CGC map (compiled by Jonathan Hodgkin) using the ACEDB program (Richard Durbin and Jean Thierry-Mieg). We also have established a World-Wide Web hypertext server to provide access to information generated by these projects. This Genetic Toolkit web site (http: genetic balancers and transgenic strains available from our laboratories. For stable transgenic strains, listed cosmids are linked to modified GenBank entries describing the sequence. This work is funded by the NIH National Center for Research Resources (NCRR) and the Canadian Genome Analysis and Technology Program (CGAT).

Hodgkin JA et al. (1994) Worm Breeder's Gazette "Possible Involvement of a Predicted RNA-Binding Protein in Primary Sex Determination."

Albertson DG, Hodgkin JA, Zellan JD

[Worm Breeder's Gazette, 1994]

Possible involvement of a predicted RNA-binding protein in primary sex determination Jonathan Hodgkin, Jonathan Zellan and Donna Albertson (MRC-LMB, Hills Road, Cambridge CB2 2QH, England) The duplications eDp26 ('xol brother') and mnDp73 together define a region of the X chromosome, between lin-32 and unc- 2, which is likely to contain a major numerator site for the assessment of X:A ratio, and hence for primary sex determination. As previously described, (WBG 13-2: 43, 1994), we have identified a locus on the physical map that may correspond to this numerator. Transgenic him-8 animals carrying extrachromosomal arrays of certain cosmids, marked with the dominant Rol plasmid pRF4, segregate wildtype hermaphrodites and wildtype males, numerous Rol hermaphrodites but almost no Rol males. Subsequent experiments have demonstrated that these arrays exert a dominant Xol (XO lethal) effect, feminize 2X:3A triploids, and have genetic properties consistent with increased numerator activity. The locus responsible has been termed 'fox-l', for 'Feminizing site On X'. Further delimitation of fox-l was carried out by testing each of !iX cosmids in the region (see figure below), as well as various derived plasmids. R04B3, F16El, and F53B5 all exert a strong (99-100%) Xol effect. T13H8 is wholly negative and turns out to be wrongly assigned to this part of the physical map. F33H6 exerts a weak Xol effect, and T07D1 is consistently negative, but coinjection of F33H6 and T07D1 leads to an array with a strong Xol effect. Together these results suggest that the overlap between F33H6 and T07D1 contains an essential part offox-l. A cDNA hybridizing across part of this overlap has been obtained, from the embryonic cDNA library constructed by Pete Okkema et al. This cDNA has been sequenced, and contains one long ORF of 401 amino acids. The predicted protein includes an excellent match to the 90 aa RNP consensus, the best characterized of RNA binding domains. At present, there is no proof that the Fox effect arises from overexpression of this particular transcript, though this hypothesis can obviously be tested. However, the circumstantial evidence is suggestive, and the possibility that an RNA-binding protein is involved in primary sex determination in C. elegans is definitely thought-provoking.