New research suggests that controlling
cytoskeletal dynamics in sperm accessory cells may help regulate male
fertility.
A
microtubule-regulating enzyme integral to spermiogenesis may be target for
future male contraceptive or fertility treatments, according to research
published today (May 24) in PLoS Genetics. An international team of researchers
identified a new enzyme, KATNAL1, which appears to regulate spermatid
maturation in mice by controlling the cytoskeleton dynamics central to sperm
cell development. Scientists hope
elucidation of KATNAL1’s role in spermiogenesis may illuminate previously
unknown causes of male infertility or provide a target for non-hormonal male
contraceptive strategies.
“It’s
an important study,” said Yan Cheng who investigates male contraception at the
Population Council in New York and was not involved with the study. Cheng noted
that it is the first study to report how loss of a microtubule-regulating
enzyme affects sperm maturation and opens the possibility of using strategies
to block or delete the enzyme as reversible or permanent contraception.
“It’s
often hard to work out why [men are infertile],” explained lead author Lee
Smith of Queen’s Medical Research Institute in Edinburgh, Scotland. In order to
shed more light on possible mutations responsible for male infertility, Smith
and his collaborators treated mice with a mutagenic chemical and screened males
for infertility. A point mutation conferring male-only infertility and smaller
testis size was mapped to a new gene, which Smith’s group called KATNAL1
(KATANIN p60-related microtubule severing protein Katanin p60 subunit A-like1),
after its high homology to KATANIN p60, an enzyme known to regulate microtubule
dynamics.
Though
KATNAL1 was expressed in a variety of tissues, including brain and liver, only
the testes of mice with a mutated form of the gene appeared grossly abnormal,
with smaller than normal testes. Overexpression of KATNAL1 in a human embryonic
kidney cell line demonstrated a similar effect on the cytoskeleton as KATANIN,
which regulates microtubule dynamics by severing microtubule filaments.
The
mutation in the infertile mice is localized to the ATP-binding domain of
KATNAL1, and appears to ablate its function. In the KATNAL1-mutated mice,
mature sperm cells were largely absent. Instead, the researchers found
prematurely-exfoliated immature cells in the epididymis, and fluorescent
imaging of microtubules in Sertoli cells showed that mutated KATNAL1 expression
correlated with fewer stable microtubules.
Cytoskeleton
dynamics are a critical regulator of sperm cell maturation. A specialized set
of polarized cells, called Sertoli cells, chaperone post-meiotic sperm cells as
they develop from a round, cytoplasm-rich immature state to their lean mature
state, having grown tails and lost excess cytoplasm. Sperm are closely
associated with Sertoli cells during their development, like apples on an apple
tree, explained Smith, and rely on them for nutrients and transport to the
lumen of the seminiferous tubules. Like apples, mature sperm will “drop off”
(known as exfoliation) when “ripe.” The transport and delivery of nutrients to
the sperm depends on dynamic microtubule filaments.
“We’ve identified
a novel pathway important in male fertility,” said Smith, who said he hopes
that further investigations will illuminate other players involved in KATNAL1
regulation and microtubule dynamics in sperm maturation. It may be possible
that KATNAL1, or a different component of this microtubule-regulating pathway,
could be a non-hormonal target for a male contraceptive drug, Smith added.
Non-hormonal
male contraceptive strategies are appealing for several reasons, said Mara
Roth, an endocrinologist at the University of Washington who did not
participate in the research. Many men respond well to hormone treatment, but
about 5 to 10 percent of men don’t show a drop in sperm counts in response to
hormones, she explained. In contrast to female hormonal contraception, which
targets one egg per month, male contraceptive strategies need to deal with the
extraordinary number of sperm produced on a daily basis—upwards of 1000 per
second. And even after vasectomies, Roth noted, some men don’t follow up to
make sure their sperm count has dropped. The challenge in using KATNAL1 as a
possible target of contraceptive drugs, she said, is in ensuring that their
action will be both reversible and restricted to the testes.
Other
scientists agreed that determining KATNAL1’s role in cells beyond Sertoli cells
is an important next step. Cytoskeleton regulation within sperm cells is also
an important component of germ cell maturation, said Ann Sperry, who studies
sperm head shaping at East Carolina University and was not involved with the
study. Some sperm did appear to mature in KATNAL1-mutant mice, but it’s unclear
if their cytoskeletons are also dysregulated, and whether this also contributes
to the infertility phenotype.
“KATNAL1
opens promising and interesting avenues to further research on this theme as
demonstrated in this beautiful scientific contribution,” R.-Marc Pelletier, who
investigates sperm maturation and infertility at the University of Montreal and
was not involved with the research, wrote in an email. “Additional information
on the systemic and topical enzymatic activity of the enzyme could contribute
to clarify its real implication in the regulation of male fertility. However,
the full resonance for future treatment of male fertility and the development
of non-hormonal male contraceptives based solely on the use of KATNAL1 may
require more supportive investigation.”
In the
meantime, Smith hopes that KATNAL1 may help researchers understand more
mechanisms underlying human male infertility. He and his collaborators hope to
discover more regulators of microtubule dynamics in Sertoli cells. If this
pathway proves to underlie infertility in men, there is a possibility of using
gene therapy to reverse it, said Smith, whose group is currently attempting
this feat in KATNAL1-mutated mice.
L.B. Smith et al., “KATNAL1 Regulation of Sertoli
Cell Microtubule Dynamics Is Essential for Spermiogenesis and Male Fertility,” PLoS Genetics,
8(5): e1002697, 2012.
Sabrina Richards
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