Scientists identify a gene that controls the timing of precisely ordered events during maturation

C. elegans is a tiny transparent worm that has proven to be a powerhouse model for understanding animal development. The developmental process is hard-wired and every cell division happens the same way and at same time in each animal. A team of researchers led by CSHL Assistant Professor Christopher Hammell used these organisms to identify a key regulator of developmental timing. As shown here, they tagged genes with a fluorescent marker, which allowed the team to visualize how an individual gene functions during development. The team identified LIN-42, a gene that is found in animals across the evolutionary tree, as a potent regulator of numerous developmental processes. Credit: C. Hammell, Cold Spring Harbor Laboratory

Closely related organisms share most of their genes, but these similarities belie major differences in behavior, intelligence, and physical appearance. For example, we share nearly 99% of our genes with chimps, our closest relatives on the great "tree of life." Still, the differences between the two species are unmistakable. If not just genes, what else accounts for the disparities? Scientists are beginning to appreciate that the timing of the events that happen during development plays a decisive role in defining an organism, which may help to explain how species evolve without the creation of new genes.

Today, a team of scientists at Cold Spring Harbor Laboratory (CSHL) has identified a key regulator of developmental timing. Led by CSHL Assistant Professor Christopher Hammell, the researchers describe how LIN-42, a gene that is found in animals across the evolutionary tree, governs a broad range of events throughout development.

"A great deal of science is focused on understanding how a single gene functions in the cell," says Hammell. "But we are learning that when a gene is active is just as important as what it does."

An organism develops in well-defined stages: nerves and muscles mature before reproductive tissues, for example. The stages unfold sequentially, like movements in a symphony. Played all at once, they would produce a terrible developmental cacophony, but with proper timing, a natural harmony can emerge.

Developmental stages are marked by the activation or repression of a specific and unique complement of genes, like individual notes within movements of a song. The order and duration of when these key (or notes) are active (or played) within a given cell is controlled by a class of molecules called microRNAs (miRNAs). A single miRNA gene can control hundreds of other genes at once. If a miRNA turns off these specific genes too early or too late, the organism will suffer severe developmental defects. But little is known about how the activities of these miRNAs are regulated.

In work published today in PLoS Genetics, Hammell and his team describe the genetic approach they used to search for genes that control developmental timing through miRNAs. The team uses a tiny roundworm, called C. elegans, as a simple model for the events that occur during development, even in higher organisms. These worms have a fixed number of cells and each cell division is precisely timed. "It is the perfect model for our work," says Hammell. "It enables us to understand exactly how a mutation affects development, whether maturation is precocious or delayed, by directly observing defects in the timing of gene expression."

The team's search uncovered the gene LIN-42 as a crucial regulator of developmental timing via its pervasive role in controlling miRNAs. "LIN-42 shares a significant amount of similarity to the genes that control circadian rhythms in organisms such as mice and humans," says Roberto Perales, PhD, one of the lead authors of the study. "These are genes that control the timing of cellular processes on a daily basis for you and me. In the worm, these same genes and mechanisms control development, growth, and and this system will provide us with leverage to understand how all of these things are coordinated."

Hammell and his team found that LIN-42 controls the repression of numerous genes in addition to miRNAs. They also discovered that levels of the protein encoded by LIN-42 tend to oscillate over the course of development and form a part of a developmental clock. "LIN-42 provides the organism with a kind of cadence or temporal memory, so that it can remember that it has completed one developmental step before it moves on to the next," says Hammell. "This way, LIN-42 coordinates optimal levels of the required throughout ."

This work was supported by the Rita Allen Foundation of which CMH is a Milton E. Cassel Scholar, the National Institutes of Health, and the Robertson Research Fund of Cold Spring Harbor Laboratory.

More information: "LIN-42, the Caenorhabditis elegans PERIOD homolog, negatively regulates microRNA transcription" appears online in PLOS Genetics on July 17, 2014. The authors are: Roberto Perales, Dana King, Christina Aguirre-Chen, and Christopher Hammell.

add to favorites email to friend print save as pdf

Related Stories

Recommended for you

Mice and men share a diabetes gene

Sep 11, 2014

A joint work by EPFL, ETH Zürich and the CHUV has identified a pathological process that takes place in both mice and humans towards one of the most common diseases that people face in the industrialized ...

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
not rated yet Jul 17, 2014
http://www.plosge....1004486

"... it is interesting to speculate how their temporal expression patterns, and levels, are coordinated with their targets."

While others find their speculation to be interesting, it's been more interesting for me to model epigenetic cause and effect via cell type differentiation in species from microbes to man and see my series of published works ignored.

Meanwhile, social scientists continue to tout their pseudoscientific nonsense. If not for the experimental evidence that shows how the pattern of feeding and nutrient-dependent pheromone-controlled amino acid substitutions can cause the differences in morphological and behavioral phenotypes of C. elegans and P. pacificus, the nonsense from social scientists might have continued indefinitely.

Focus on the nutrient-dependent pheromone-controlled microRNA/messenger RNA balance will change everything you thought you knew about evolution versus ecology.
JVK
not rated yet Jul 17, 2014
"Clearly, gene expression is somehow controlled by epigenetic effects on transcribed small RNAs [6]. Experimental evidence suggests nutrient-dependent epigenetic effects on vitamin-dependent base pair changes lead from changes in the miRNA/mRNA balance to amino acid substitutions and the differentiation of cell types. That makes it possible to begin with nutrient-dependent changes in base pairs and to tentatively arrive at the morphological and behavioral phenotypes of different species based on what is currently known about the involvement of the miRNA/mRNA balance in species diversity. Simply put, nutrient-dependent pheromone-controlled ecological adaptations via amino acid substitutions [30] appear to require fine-tuning of conserved molecular mechanisms in species from microbes to man [31]. The nutrient-dependent miRNA/mRNA balance is probably responsible for that fine-tuning in plants and in animals." Kohl (unpublished)

VIDEO: http://youtu.be/DbH_Rj9U524
JVK
not rated yet Jul 17, 2014
Nutrient-dependent pheromone-controlled feedback loops control the timing of precisely ordered events during maturation in my model.

http://www.ncbi.n...24693353

See also: http://www.pnas.o...abstract

"Larvae on the pheromone-containing plates entered the extended, predauer L2d stage, whereas larvae on the plates without exogenous pheromone developed through the rapid L2 stage."

For evidence of ecological speciation sans mutation-initiated natural selection and the evolution of biodiversity see: System-wide Rewiring Underlies Behavioral Differences in Predatory and Bacterial-Feeding Nematodes http://linkinghub...12015000
anonymous_9001
not rated yet Jul 17, 2014
Once again, you demonstrate your ignorance of the difference between expression and sequence of DNA. Species are not only distinguished by epigenetic differences, but also by genetic differences that your model does not take into consideration at all. Splicing does not alter DNA sequence.
JVK
not rated yet Jul 18, 2014
The anonymous fool should identify himself as Andrew Jones, who is the author of

"Criticisms of the nutrient-dependent pheromone-controlled evolutionary model"

http://www.socioa...67/34076

Andrew's complaints have been dealt with in the context of peer-review of my most recent published work. Complaints by others can be viewed in the light of what is currently known about molecular biology, which shows that nothing about evolution makes sense except in the context of how ecological variation leads to cell type differentiation by nutrient-dependent amino acid substitutions that stabilize the organized genome and result in ecological adaptations.
anonymous_9001
not rated yet Jul 18, 2014
Took you long enough. Regardless, you have yet to address my previous post. The basis of your model, splicing and other eoigenetics processes, do nothing to the genes themselves.
JVK
not rated yet Jul 18, 2014
http://www.the-sc...plexity/ Excerpt: "...have now uncovered almost 250 protein splice variants of an essential, evolutionarily conserved family of human genes."

The conserved molecular mechanisms of epigenetically-effected nutrient-dependent pheromone-controlled alternative splicings of pre-mRNA that enable cell type differentiation via amino acid substitutions that stabilize the organized genomes of species from microbes to man has been my focus for more than 20 years.

Across species examples are included in my 2013 review:

Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353

Andrew Jones' criticisms were dealt with by the editor of the journal, who politely attested to the fact that Andrew Jones is a fool (i.e., one of many among PZ Myers' idiot minions).

Conserved molecular mechanisms exemplify ecological adaptations, not evolution.
anonymous_9001
not rated yet Jul 18, 2014
Andrew Jones' criticisms were dealt with by the editor of the journal, who politely attested to the fact that Andrew Jones is a fool (i.e., one of many among PZ Myers' idiot minions).


Explain.
JVK
not rated yet Jul 18, 2014
You (the anonymous fool and idiot minion) wrote: "James Kohl presents an unsupported challenge to modern evolutionary theory and misrepresentations of established scientific terms and others' research."

Harold Mouras wrote: The 2013 review article by James Vaughn Kohl published in Socioaffective Neuroscience & Psychology and criticized in the above Letter to the Editor was subjected to standard peer review and the revised version was accepted by me after it had been accepted by both reviewers.

You wrote: "Proteasomes... are actually structures whose function is to break down proteins."

See Added Layers of Proteome Complexity http://www.the-sc...plexity/

Address the content of my published works, not the nonsense you have added in the context of PZ Myers' ridiculous blog.
anonymous_9001
not rated yet Jul 19, 2014
Kohl, the king of misinterpretations, unsurprisingly misinterprets Mouras' note. If he thought I was a fool, he wouldn't have published it.

You wrote: "Proteasomes... are actually structures whose function is to break down proteins."

See Added Layers of Proteome Complexity http://www.the-sc...plexity/


You're mixing up terms again. Proteasome =/= proteome.
JVK
not rated yet Jul 19, 2014
I wrote: "Address the content of my published works, not the nonsense you have added in the context of PZ Myers' ridiculous blog."

"...the model represented here is consistent with what is known about the epigenetic effects of ecologically important nutrients and pheromones on the adaptively evolved behavior of species from microbes to man. Minimally, this model can be compared to any other factual representations of epigenesis and epistasis for determination of the best scientific 'fit'."

http://www.socioa...53/27989

What are you trying to tell others about the involvement of proteasomes in the context of the evolution of biodiversity?

anonymous_9001
not rated yet Jul 20, 2014
Completely ignoring the fact that you're confusing proteasomes and the proteome. Typical. This conversation will go nowhere until you correct your mistake. Otherwise, I have no idea what you actually mean. As you've already been told, you must clearly establish what you're talking about before you can actually talk about it. If you're mixing up and redefining terms, then the discussion participants aren't on even ground.

I added no "nonsense in the context of PZ Myers' blog". Everything I added was factual and logical and sourced directly from you, whether it was from your published works or external discussion. Context can be clearly established by going back to the source. My letter was also quite a bit longer before Mouras told me to focus more on your publications rather than your numerous fallacy and error-filled comments scattered around the web.
anonymous_9001
not rated yet Jul 20, 2014
.
JVK
not rated yet Jul 20, 2014
Cell type differentiation is nutrient-dependent and pheromone-controlled via conserved molecular mechanisms in species from microbes to man.

If you have an alternative to that biological fact, please tell us about how you think biodiversity evolved and include examples from model organisms.
JVK
not rated yet Jul 20, 2014
Effects of starvation can be passed to future generations, through small RNAs apparently without DNA involvement http://www.scienc...4600.htm

How is it possible that PZ Myers and his idiot minions as well as the anonymous fool (Andrew Jones) have missed out on every biological fact that led to the above claim?
JVK
not rated yet Jul 20, 2014
My letter was also quite a bit longer before Mouras told me to focus more on your publications...


Thanks for mentioning that. Do you think he "baited" you into the admission that you have no knowledge of molecular biology compared to what we first offered in the context of our 1996 Hormones and Behavior review? http://www.ncbi.n.../9047261

"Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes." (p. 337)
anonymous_9001
not rated yet Jul 21, 2014
Why you continue to insist that anybody is denying eoigenetics is beyond me. How is "the effect of starvation..." at odds with anything I or anybody else has said? Be specific.

Do you think he "baited" you into the admission...


What admission? What on earth are you babbling about?
JVK
not rated yet Jul 21, 2014
You cited my comment at: http://freethough...-page-1/

"Ecological adaptation occurs via the epigenetic effects of nutrients on alternative splicings of pre-mRNA which result in amino acid substitutions that differentiate all cell types of all individuals of all species. The control of the differences in cell types occurs via the metabolism of the nutrients to chemical signals that control the physiology of reproduction.
These facts do not refute evolution; they simply refute the ridiculous theory of mutation-initiated natural selection that most people here were taught to believe is the theory of evolution.
That theory is far too ridiculous to be anything but a joke in the context of biological-based increasing organismal complexity."

If you claim that mutation-initiated natural selection causes the evolution of biodiversity, you need to explain how it does it. Be specific.
anonymous_9001
not rated yet Jul 21, 2014
Cell types within the same organism are differentiated epigenetically. Genetic changes, however, differentiate species, and genetic changes are not the result of epigenetic processes. Mutations cause alterations in DNA sequence. Epigenetics only concerns the EXPRESSION of genes.

Which part of that summary do you disagree with?