No NELL2, no sperm motility; novel protein is essential for male
fertility

Date:
July 9, 2020
Source:
Baylor College of Medicine
Summary:
An international team of researchers has identified a chain of
events that matures the sperm and triggers their motility. The
findings have implications for diagnostic and therapeutic research
in male infertility and male contraceptive development.



FULL STORY ========================================================================== Newly produced spermatozoa within the testis are not fully functional
until they mature in the epididymis, a duct that helps to transport and
store sperm.

Male infertility may arise from lack of communication between the testis
and the epididymis and new research has uncovered a mechanism of this communication.


==========================================================================
Dr. Martin Matzuk at Baylor College of Medicine, Dr. Masahito Ikawa with
Osaka University and their colleagues have discovered a novel testicular luminal protein, NELL2, that triggers in the epididymis a chain of events
that matures the sperm and enables each one to be motile in females.

Sperm production Sperm are produced in the seminiferous tubules of the
testis and move through the epididymis, a long, convoluted tube linked
to the vas deferens, the duct that moves sperm from the testicle to
the urethra. When the sperm enter the epididymis, they are not motile
and are incapable of fertilization. However, in their passage through
the epididymis, the sperm are provided an appropriate environment for maturation and storage pending ejaculation.

It has been hypothesized that proteins released by the testis earlier
in this process could act on the epididymis to mature the sperm as they
arrive in the epididymis.

"Until now the proteins working through the lumicrine system of
signaling have remained elusive. While it was known that the orphan
receptor tyrosine kinase ROS1 expressed in the initial segment of the epididymis is necessary for its differentiation, neither the testicular
factors that regulate initial segment differentiation nor the process
of sperm maturation had been fully understood," said Matzuk, professor
and director of the Center for Drug Discovery at Baylor.

Identifying NELL2 The researchers zeroed in on NELL2, a protein factor
secreted by testicular germ cells, as a possible lumicrine regulator
of fertility. "Using innovative genome editing technology, we generated knockout mice lacking the NELL2 gene and showed that these knockout males
are sterile due to a defect in sperm motility," explains lead author
Dr. Daiji Kiyozum. "Moreover, their infertility could be rescued with a germ-cell-specific transgene, thus excluding other sites of expression. We
also illustrated lumicrine signaling by demonstrating tagged NELL2 in
the epididymal lumen." The research team observed that spermatogenesis proceeds normally in NELL2 knockout mouse testes but their epididymis was poorly differentiated, similar to Ros1 knockout mice. Following mating,
neither NELL2 knockout nor Ros1 knockout spermatozoa can enter the uterine tubes or fertilize an egg. Further investigation showed that the Nell2
knockout epididymis is incapable of processing a specific sperm surface
protein essential for male fertility.

Implications for male fertility? Elaborating on their study, Ikawa
and Matzuk, both senior authors, said, "We discovered a complicated
cascade of events in which disruption of any point in this lumicrine
pathway causes a male to be infertile. Our findings have important translational implications for diagnostic and therapeutic research
in male infertility and male contraceptive development. This unique transluminal communication pathway between tissues and organs likely
functions elsewhere in our bodies."

========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Graciela Gutierrez. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Daiji Kiyozumi, Taichi Noda, Ryo Yamaguchi, Tomohiro Tobita,
Takafumi
Matsumura, Kentaro Shimada, Mayo Kodani, Takashi Kohda, Yoshitaka
Fujihara, Manabu Ozawa, Zhifeng Yu, Gabriella Miklossy, Kurt
M. Bohren, Masato Horie, Masaru Okabe, Martin M. Matzuk, Masahito
Ikawa. NELL2- mediated lumicrine signaling through OVCH2 is
required for male fertility. Science, 2020; 368 (6495): 1132 DOI:
10.1126/science.aay5134 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200709135625.htm

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