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Caenorhabditis elegans
In a recent study published in Nature Communications, Dr.
Emily Spaulding and Dr.
Dustin Updike discovered a homologue of a well-known human protein nucleolar protein in Caenorhabditis elegans
, a small transparent worm.
Nucleolin has been linked
to neurodegenerative diseases and cancer in humans.
However, this new finding challenges recent theories that intranuclear structures may play a role in this disease and provides powerful new tools
for studying the function of nucleolins and their contribution to disease.
"Nucleolin is a versatile protein that is conserved in many animals, plants, and fungi, but was previously thought to be absent in nematodes," said
Spaulding, a postdoc in Updike's lab at the Desert Island Mountain Biological Laboratory.
"It is also associated with familial ALS and Alzheimer's disease, and global nucleolar dysfunction is associated
with neurodegeneration.
"
Their identification of nucleolin homologs (named NUCL-1) laid the foundation
for a new discovery platform for nucleolin neuronal function and related neurodegenerative disease genetics in Caenorhabditis elegans.
The image on the left is a super-resolution image of the nucleoli of the wild-type Caenorhabditis elegans, showing the good tissue structure
of the internal coagulate.
In the image on the right, the structure breaks down
when a newly discovered coding gene called NUCL-1 is destroyed in the mutated nematodes.
Contrary to some ideas about the function of nucleolar substructures, both wild-type and mutant nematodes are healthy, develop normally, and retain fertility
.
Nucleolin is mainly found in nucleoli, which are factories
for the assembly of nucleosomes in the cell.
Unlike many other membrane-bound organelles within the cell, the nucleoli behave like a large droplet, also known as a coagulant
.
Condensate is formed
by liquid phase separation.
Some have imagined that spots of varying densities will form inside lava lamps, but exactly how this is achieved in living cells is unclear
.
Spulding and Updike's work showed that in the nucleoli of Caenorhabditis elegans, NUCL-1 is required for phase separation
.
Because nematodes are particularly well-suited to live microscopy, which can provide a close-up look at endogenous proteins inside living animals, the discovery could change scientists' perception
of the characteristics of coagulants such as nucleoli.
"The transparency of Caenorhabditis elegans allows us to perform super-resolution imaging, which allows us to see the nucleolar structure of living animals," Spaulding said
.
"I've never seen anything like this anywhere else
.
" Spaulding compares kernels to lollipops
.
"It has layers inside and out," she said
.
"Some proteins are localized in the innermost layer, while some proteins are localized in the outermost layer
.
Each layer is thought to represent a step
in ribosome biogenesis.
”
The biological significance of the condensate substructure remains an issue; Recent theories suggest that precise, hierarchical spatial organization of nucleoli is critical
for ribosome production.
But MDIBL scientists observed that after removing the key protein domain of nucleus-1 in the transgenic Caenorhabditis elegans, the nucleolar structure within the germ cells was disrupted, and the mutant nematodes still developed normally and produced normal offspring
.
"We noticed that when we removed the domain, the nucleoli lost their beautiful substructure, but the nematodes were completely fine
," she said.
This was a surprise, and it hinted that perhaps this precise hierarchical organization was not as important
for nucleolar function as we thought.
This may be important for understanding ALS or Alzheimer's disease, where widespread phase separation disruption is thought to be the cause of
the disease.
”
Updike said: "This will be something that really affects the field of phase separation because many of the
conclusions drawn may not be correct.
These results should generate widespread interest and will lead to new avenues
of research in the areas of phase separation, nucleolar structure and function, and nucleolar-related human diseases.
Spaulding is the recipient of the 2022 National Institutes of Health Distinguished Scholar Award in Neuroscience
.
References: "RG/RGG repeats in the C.
elegans homologs of Nucleolin and GAR1 contribute to sub-nucleolar phase separation" by Emily L.
Spaulding, Alexis M.
Feidler, Lio A.
Cook and Dustin L.
Updike, 3 November 2022, Nature Communications.
