Ellis RE et al. (2015) Elife "Size isn't everything."

Wei Q, Ellis RE

[Elife, 2015]

Male nematode worms may make larger sperm than hermaphrodite worms, but this is not the only reason that sperm from males have a competitive edge.

Ellis RE (2022) Sex Dev "Sex Determination in Nematode Germ Cells."

Ellis RE

[Sex Dev, 2022]

BACKGROUND: Animal germ cells differentiate as sperm or as oocytes. These sexual fates are controlled by complex regulatory pathways to ensure that the proper gametes are made at the appropriate times. SUMMARY: Nematodes like Caenorhabditis elegans and its close relatives are ideal models for studying how this regulation works, because the XX animals are self-fertile hermaphrodites that produce both sperm and oocytes. In these worms, germ cells use the same signal transduction pathway that functions in somatic cells. This pathway determines the activity of the transcription factor TRA-1, a Gli protein that can repress male genes. However, the pathway is extensively modified in germ cells, largely by the action of translational regulators like the PUF proteins. Many of these modifications play critical roles in allowing the XX hermaphrodites to make sperm in an otherwise female body. Finally, TRA-1 cooperates with chromatin regulators in the germ line to control the activity of fog-1 and fog-3, which are essential for spermatogenesis. FOG-1 and FOG-3 work together to determine germ cell fates by blocking the translation of oogenic transcripts. Key Messages: Although there is great diversity in how germ cell fates are controlled in other animals, many of the key nematode genes are conserved, and the critical role of translational regulators may be universal.

Ellis RE (2016) Mol Reprod Dev "'The persistence of memory' - Hermaphroditism in nematodes."

Ellis RE

[Mol Reprod Dev, 2016]

Self-fertility has evolved many times in nematodes. This transition often produces an androdioecious species, with XX hermaphrodites and XO males. Although these hermaphrodites resemble females in most respects, early germ cells differentiate as sperm and late ones as oocytes. The sperm then receive an activation signal, populate the spermathecae, and are stored for later use in self-fertilization. These traits are controlled by complex modifications to the sex-determination and sperm activation pathways, which have arisen independently during the evolution of each hermaphroditic species. This transformation in reproductive strategy then promotes other major changes in the development, evolution and population structure of these animals. This article is protected by copyright. All rights reserved.

Ellis RE et al. (2000) Midwest Worm Meeting "The search for mRNA targets of FOG-1"

Ellis RE, Jin S-W

[Midwest Worm Meeting, 2000]

The fog-1 and fog-3 genes are required to specify that germ cells differentiate as sperm. Although mutations in either gene cause germ cells to develop as oocytes instead, they have no effect on somatic fates. Thus, one simple model is that fog-1 and fog-3 act in response to the sex-determination genes to regulate germ cell fates. We cloned fog-1 to test this model. Northern analyses, RACE and RT-PCR experiments show that fog-1 produces four transcripts. These transcripts fall into two groups two long transcripts of 2138 and 2237 nucleotides that differ in their polyadenylation sites, and two short transcripts of 1612 and 1711 nucleotides that lack the first four exons of the long transcripts. All four messages are trans-spliced to SL1. Using RNA-mediated inactivation, we found that the large transcripts are necessary for germ cells to become sperm. Furthermore, transformation rescue experiments suggest that the large transcripts might also be sufficient for fog-1 activity. Finally, Northern analyses show that the quantity of large transcripts is regulated by the sex-determination genes. Since the promotor for the large transcripts contains potential TRA-1A binding sites, we propose that the sex-determination genes act through TRA-1A to control production of fog-1. The large transcripts encode a protein of 619 amino acids, which resembles Cytoplasmic Polyadenylation Element Binding proteins. These proteins regulate translation of target messages by controlling the lengths of their poly-A tails. Genetic and molecular tests show that nonsense mutations behave like null alleles of fog-1, but that missense mutations in the conserved RNA-binding domains have a strong dominant negative effect. This result implies that (1) the RNA binding domains are essential for FOG-1 activity, and (2) the mutant FOG-1 proteins bind to and inactivate something needed to cause germ cells to differentiate as sperm. We have found a potential target site for FOG-1 in the 3-untranslated region of the fog-1 message itself. Northwestern analyses, UV-crosslinking studies, and immunoprecipitation experiments suggest that FOG-1 can bind this site. Considering all of these results together, we propose that FOG-1 acts as part of a complex that controls translation of key messenger RNAs in the developing germ line. The proteins encoded by these messages act together to cause germ cells to become sperm rather than oocytes.

Ellis RE (2010) Nat Chem Biol "Stem cells: chemically reprogramming cell fates."

Ellis RE

[Nat Chem Biol, 2010]

Ellis RE et al. (1995) International C. elegans Meeting "Some Light in the Fog"

Ellis RE, Kimble JE

[International C. elegans Meeting, 1995]

The genes that control sex determination in C. elegans regulate dozens of individual cell fates. To understand this process, we are studying a single decision -- whether germ cells form sperm or oocytes. Both fog-1 and fog-3 play critical roles in this choice. If either gene is inactivated, germ cells that would have formed sperm instead develop as oocytes. Furthermore, analyses of double mutants suggest that fog-1 and fog-3 act downstream of other sex-determination genes. Finally, mutations in fog-1 or fog-3 show unusual interactions in combination with mutations in gld-1 (1,2), a gene required for oogenesis. New genetic and molecular experiments are consistent with the possibility that fog-1 and fog-3 interact to determine cell fate. We measured the strength of several fog-1 alleles, and found that some mutations show much stronger semi-dominance than is displayed by a deletion of the fog-1 gene or by likely null alleles. Thus, these mutant fog-1 alleles encode a product that inhibits spermatogenesis. They might interfere directly with fog-1 activity, or instead act on another sex-determination gene, such as fog-3. To understand the role of fog-1 better, we are cloning the gene. We have obtained transformation rescue with Y54E10, and have mapped fog-1 to a small region of that YAC. We are also cloning fog-3. We have obtained transformation rescue with the cosmid F14G10, and used deletion mapping to localize fog-3 to the right side of this cosmid. A 2.8 kb fragment from this region prevents spermatogenesis in transformed animals. Thus, this fragment is likely to contain part, but not all, of the fog-3 gene. We are currently sequencing the genomic DNA from this region, testing for the presence of germline specific transcripts, and screening for cDNAs.

Ellis RE (2006) Genome Biol "Enigma variations: control of sexual fate in nematode germ cells."

Ellis RE

[Genome Biol, 2006]

ABSTRACT: A new study showing that neither FEM-2 nor FEM-3 is required for spermatogenesis in Caenorhabditis briggsae, unlike in Caenorhabditis elegans, implies that the sex-determination pathway in these species is evolving rapidly, and supports the proposal that they evolved hermaphroditism independently.

Ellis RE et al. (1991) International C. elegans Meeting "PROGRESS IN CLONING fog- 1"

Kimble JE, Ellis RE

[International C. elegans Meeting, 1991]

The fog-l gene plays an important role in the decision of germ cells to differentiate as either spermatocytes or oocytes (Doniach 1986, Barton and Kimble 1990). In fog-l mutants, all germ cells develop into oocytes. This is true for both males and hermaphrodites. However, these fog-l mutations do not appear to affect other aspects of sexual development. Furthermore, the fog-l mutant phenotype is not suppressed by mutations in any of the other genes known to control sex- determination. Thus fog-l might function to initiate spermatogenesis in response to other genes that regulate general sexdetermination. There are 42 fog-l mutations. These mutations arise at a frequency typical for knockout mutations in other C. elegans genes, and four of these fog-l alleles were isolated from a screen capable of recovering deletions. Thus it is likely that these mutations cause a loss of fog- l function. In order to study the mechanisms by which fog-l functions, and to determine how fog-l expression is regulated by the genes that control sex-determination, we are now cloning this gene. The fog-l gene is located on the left arm of LGI, between sup-ll and unc-ll, a region spanned by a large contig of about one megabase in size. By mapping DNA polymorphisms with respect to fog-l, we have narrowed down the region in which fog-l must be located, and are now injecting YAC DNA that covers this region in an attempt to rescue fog-l mutants.

Ellis RE et al. (1986) Worm Breeder's Gazette "the mutation n703 prevents specific cell deaths."

Horvitz HR, Ellis RE, Sulston JE

[Worm Breeder's Gazette, 1986]

One fate shared by many cells during C. elegans development is programmed cell death. To examine the mechanisms responsible for determining cell fates, we are studying mutants in which certain cells that normally die instead survive and mutants in which cells that normally survive instead die. For example, mutations in the gene egl- 1 cause the HSNs to undergo programmed cell death. The mutation n703 results in the opposite type of transformation -- it prevents some cell deaths without affecting others. n703 was identified by Nancy Tsung and Carol Trent. Whereas wildtype animals have only two serotonergic cells in the pharynx, the NSMs, they found that n703 worms usually have four. Hilary Ellis examined the pharynx of n703 animals using Nomarski microscopy and saw one, and frequently two, extra nuclei in both the left and right subventral portions of the front bulb. All of the extra nuclei appeared neuronal. These cells could be generated either by extra cell divisions or by the survival of cells that normally die. Although 10 cells die during the development of the neurons of the front bulb of the pharynx, we usually saw the remains of only two dead cells in this region in late ced-2(e1752) embryos. (Mutations in ced-2 cause dead cell bodies to persist). n703; ced-2(e1752) worms lacked even this pair, though most other cell deaths in the head were unaffected. This result indicates that the extra cells in n703 animals may be ones that normally die. Studies of ced-3 worms have suggested that when some cells fail to undergo cell death, they adopt the fates of close relatives . We therefore wondered if the extra cells in n703 animals were closely related to known nerve cells. In the ventral portion of the front bulb of the pharynx there are five classes of nerve cells; three of these, the NSMs, I1s, and I2s, have closely related deaths that if prevented might give rise to extra pairs of cells like those we had observed. Since one pair of extra cells is serotonergic, we expected that these cells might be the surviving sisters of the NSMs (which are also serotonergic). Direct observation confirmed that in n703 animals the NSM sisters do not die at the normal time, and spot checks showed that they survive throughout embryogenesis. The I2 sisters also survive, so we suspect that they may be the other pair of extra cells found in n703 worms. However, additional cell death survivors may also exist. Carol Trent showed earlier that in n703 animals the presence of extra serotonergic cells is a dominant phenotype. We have quantified this dominance by counting nuclei in the pharynx. n703 is 100% penetrant in homozygotes (124/124 animals) and about 94% penetrant in heterozygotes (140/149 animals). Expressivity is variable in both cases, with all four extra cells present much more frequently in homozygotes. We have mapped n703 slightly left of unc-29 on chromosome I (2/13 Unc-29 nonDpy-14 and 3/4 Dpy-14 non-Unc-29 recombinants segregated n703) and are now working to define the null phenotype of the gene.

Ellis RE et al. (1989) International C. elegans Meeting "genetic analysis of programmed cell death."

Horvitz HR, Ellis RE

[International C. elegans Meeting, 1989]