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Gene & Protein in Disease MPDZ regulates sperm motility

potential. Here, we show that MPDZ acts as a regulator of
A B sperm motility in mice. MPDZ knockout led to reduced
sperm motility, including fast-, medium-, and progressive
motility. Meanwhile, MPDZ expression in human sperm
tends to show positive correlations with sperm motility,
as well as forward progressive motility and fast-forward
progressive motility. Moreover, we find that MPDZ is
localized in the principal piece of the sperm flagellum
(Figure S4), and we think that it is the structural basis for
C MPDZ functionally regulating sperm motility. However,
this discovery differs from previous studies, which revealed
that MPDZ was detected only in the head of mammalian
sperm [41-43] . This discrepancy in localization may be due to
sperm fixation methods or the epitope of proteins used as
immunogens and/or the different spatial conformational
epitopes [44,45] . Of course, further exploration is required.
Combined with the fact that MPDZ expression is
beneficial for sperm motility in human and murine sperm,
we suppose that MPDZ could be a candidate for clinical
asthenospermia therapy.

Figure 5. Visualization of the structure in the center of the most The importance of intracellular Ca signals in regulating
2+
populated cluster in docking Stat3 (ligand) to MPDZ (receptor) using sperm motility has been elegantly shown in recent studies.
PyMol. The docked ligand structure is shown as a cyan cartoon (A) or Over the past two decades, direct electrophysiological
magenta cartoon (B), whereas the receptor is shown as a grey surface.
(C) Schematic diagram of sperm motility regulation by MPDZ. MPDZ recordings, together with experimental results involving
bound to Stat3 and promoted its phosphorylation at Y705 (green dots) to genetically modified mouse models and human genetics,
upregulate the CatSper1/2 expression, which would improve the cell Ca have confirmed the importance of the principal Ca -selective
2+
2+
signal and maintain sperm motility. plasma membrane ion channel CatSper for the influx of
Abbreviation: MPDZ: Multiple PDZ domain protein.
Ca . CatSper is a unique family of sperm cation channel-
2+
networks [35,36] . We explore the interaction between MPDZ like proteins expressed exclusively in the testes and function
and Stat3 using Cluspro Sever, a popular Web server for the as a polymodal sensor that translates physical and chemical
2+
[8]
direct docking of two proteins [37,38] . As shown in Figure 5, signals in the reproductive tract into a Ca response .
2+
interactions of MPDZ-Stat3 were observed between the CatSper-mediated Ca signaling is integrated into various
7 PDZ domain of MPDZ (PDB: 2IWQ) and mouse Stat3 sperm behaviors, including directed chemotactic turns,
th
[16]
(PDB: 4ZIA), between the 12 PDZ domain of MPDZ random turning, and hyperactivation . The activation
th
(PDB: 2IWP) and mouse Stat3 (PDB: 3CWG). According of the CatSper channel by intracellular alkalinization as
to the substantial number of low energy docked poses well as various physiological ligands and chemicals at the
[46]
cluster in a narrow vicinity of MPDZ-Stat3 complex, we translational level has been elucidated in detail . Here,
could reasonably assume that there is a well-defined free we find that the MPDZ gene acts as an activator in the
energy well around the native complex of MPDZ-Stat3. CatSper channel by transcriptionally regulating CatSper1/2,
thus leading to an increase in the intracellular Ca signal
2+
4. Discussion of GC2 cells. However, the expression of CatSper4 was not
detected in GC2 cells. This could be explained by the fact
MPDZ is one of the components of the Crumbs that CatSper4 expression begins in meiotic and post-meiotic
complex , which plays an important role in cell sperm cells , while GC2 is a kind of cell derived from
[39]
[47]
migration. Historically, it has been acknowledged that the spermatocytes before meiosis .
[48]
crumbs complex functioned as a tumor suppressor, as its
loss would induce cancer cell migration and invasion by Except for the translational level, transcriptional
altering cell polarity . Recent work shows that MPDZ regulation of the CatSper has attracted more attention
[40]
inhibits the migration of lung cancer cells by activating recently. The HMG-box family of proteins is required
the Hippo signal . These results suggest that MPDZ is an for murine CatSper1 transcription. The murine Catsper1
[29]
important regulator of cell motility. Sperm is a structurally promoter is responsive to Sox5, Sox9, and the sex-
specialized terminal differentiated cell with high motility determining region Y (SRY) [49,50] . The family of proteins
Volume 2 Issue 2 (2023) 8 https://doi.org/10.36922/gpd.397