YSM Issue 97.1

Genetics
FOCUS
hollow, tubular structures that run
along the flagellum. These microtubules
are connected in the core of flagella by
T-shaped multiprotein complexes called
radial spokes. Made up of “head” and
“stalk” components, radial spokes are
essential for controlling how the cilia and
flagella beat—and by extension, controlling
how sperm move.
The researchers demonstrated that
the protein LRRC23 is a crucial head
component of a specific radial spoke, radial
spoke 3 (RS3). Chung’s team collaborated
with the Zhang lab in Yale’s Department
of Molecular Biophysics and Biochemistry
to use a technique called cryo-electron
tomography, a powerful imaging tool that
bombards frozen samples with electrons to
create high-resolution, three-dimensional
representations of molecular structures.
The advantage of cryo-electron tomography
is that live samples can be observed on a
highly magnified scale. “This technique is
now the leading technique in structural
biology,” Chung said.
Chung’s team was able to visualize the
structure of sperm with and without
the genetic mutation. In samples where
LRRC23 was defective, the entire head
region of RS3 was missing. This affected
how the microtubules in sperm cilia and
flagella interacted, leading to decreased
sperm motility.
Flipping the Script on LRRC23
Before this study, scientists thought that
LRRC23 was a stalk protein rather than
a head protein. Indeed, it was believed
that LRRC23 was a homolog of the RS2
stalk protein RSP15—in other words,
researchers thought LRRC23 and RSP15
shared a common ancestor and therefore
might have similar functions. The
problem, Chung’s team realized, was
that RSP15 is a protein found in a type
of algae called Chlamydomonas—and
RS3 in Chlamydomonas doesn’t have a
head component.
To put this long-held notion to the test,
the scientists used biochemical analyses to
track the evolution of LRRC23 and observe
its interactions with other proteins. If
LRRC23 were indeed a stalk protein, it
would have been expected to interact with
other known stalk proteins. Instead, it
only interacted with head proteins.
“We actually found out that LRRC34, not
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LRRC23, looked like a mammalian RSP15
homolog, which conflicts with the major
paradigm in the field,” Chung said. She
and her team concluded that LRRC23
must be a head protein—specifically, a
head component of RS3. This critical
discovery gives researchers new insights
into the structure and function of LRRC23.
The journey to this finding was not
without obstacles. Halfway through the
study, another research team published
an article making similar connections
between the gene Chung’s team was
studying and male infertility. “It was
disappointing in the moment,” Chung
said. But Jae Yeon Hwang, the first
author of the study, didn’t give up.
He encouraged the team to continue
studying LRRC23, and they ultimately
discovered the protein’s role as a head
rather than stalk protein. “We were able
to make a different conclusion which
turned out to be validated at multiple
levels, including evolution, genetics,
biochemistry, and structure,” Chung said.
“It was a comprehensive and satisfying story
as a scientist and highlights the power of
interdisciplinary collaboration.”
But the story doesn’t end here. The
team plans on pushing their work up to
the atomic resolution. “Our next step
is doing a proteomic study to really
figure out the molecular composition
and architecture of the radial spoke
protein,” Chung said. This entails a
comprehensive examination of all the
proteins present in a biological sample,
which will give researchers even more
information about how exactly LRRC23
dysfunction causes male infertility.
ABOUT THE AUTHOR
Clinical Implications
For Chung, the most satisfying part of her
research is its potential translation into clinical
practice. “This study in particular is linked
to real, human patients,” she said. Identifying
genes that reduce sperm motility will allow
couples to be more informed about their
fertility journeys. With a comprehensive,
compiled list of genes causing fertility defects,
clinics can conduct genetic screening to
inform clients of their chances of conception.
Further, they can tell couples if their future
children might have a risk of being infertile
when they grow up.
“By human nature, [couples] not only want
to get treated, they also want to understand
why they can’t conceive,” Chung said. Once
couples have a better scientific understanding
of why they might be infertile, it becomes
easier to suggest treatment or new options
for conception.
There is still hope for patients with defective
LRRC23 proteins. A technique called
intracytoplasmic sperm injection can be
used on men who have low sperm motility.
Intracytoplasmic sperm injection is a type
of in vitro fertilization in which a healthcare
provider chooses a healthy-looking sperm
and uses a needle to inject this sperm directly
into an egg. Then, the resulting embryo is
transferred to the uterus of the female partner.
“The success rate may be low, but they
can still conceive,” Chung said. “The
process can be mentally, physically, and
emotionally painful for women.” Chung
hopes that her team’s work will lead to a
better understanding of the regulatory
mechanisms behind low sperm motility—
and to better chances for conception. ■
ANYA RAZMI
Anya Razmi is a senior in Pierson majoring in English with a Concentration in Writing. In addition
to writing for YSM, she is a content designer, a Writing Partner, an Academic Strategies mentor,
an editor for the literary magazine The Foundationalist, and is working to create a novel menstrual
product with the startup Sprxng.
THE AUTHOR WOULD LIKE TO THANK Dr. Jean-Ju Chang for her time and dedication to her work.
REFERENCES:
Hwang, J. Y., Chai, P., Nawaz, S., Choi, J., Lopez-Giraldez, F., Hussain, S., Bilguvar, K., Mane, S.,
Lifton, R. P., Ahmad, W., Zhang, K., & Chung, J.-J. (2023). LRRC23 truncation impairs radial
spoke 3 head assembly and sperm motility underlying male infertility. eLife, 12. https://doi.
org/10.7554/elife.90095.3
March 2024 Yale Scientific Magazine 13