A knock-in mouse model for male fertility: basis for the mammal-specific protein phosphatase isoform PP1y2 in sperm - Spermatogenesis and the development of fertility competent sperm involve complex
processes in the testis, epididymis and female reproductive tract. These physiological processes
of sperm formation and development are difficult if not impossible to be recapitulated and studied
in vitro. Mouse models amenable to genetic manipulation are essential for understanding the basis
for male gamete function.
Considerable progress has been made in identifying signaling proteins essential for
sperm function which include components of cyclic AMP metabolism, proteins controlling sperm
intracellular pH and calcium levels of sperm in the epididymis and in the female reproductive tract.
Numerous gene knock out approaches targeting the signaling proteins involved in metabolism and
in the action of second messengers result in male infertility. Yet the mechanistic basis for normal
and disrupted sperm function remains largely unknown.
We discovered that a protein phosphatase PP12, which is one of two paralogs from
one gene Ppp1cc, is highly expressed in testis and present in sperm. The other paralog, PP11, is
expressed in brain and several somatic cells and tissues and cells. Two other genes encode the
PP1 and PP1 isoforms. These four PP1 isoforms are highly conserved between themselves and
across species. The isoform PP12 is present only in placental mammals suggesting an essential
role for it in the unique features of mammalian sperm function. It is notable that sperm from other
species contain one of the protein phosphate isoforms PP11, PP1 or PP1. The targeted knock
out of Ppp1cc results in male infertility. Transgenic expression of PP12, but not PP11, driven by
a testis specific promoter restores fertility in the Ppp1cc null mice, highlighting the essential
requirement for PP12. In this proposal we will examine a mouse line we have generated where
the Ppp1cc gene is edited by Crispr/Cas9 to express PP11 alone in testis. Determination of the
impaired functions in PP11 bearing mice and sperm should lead to the identification of key proteins
essential for normal sperm function.
Male infertility is responsible for about 10% of infertile couples. Identification of the
causes and treatments for male infertility are limited. A number of factors can affect male infertility:
major factors are likely environmental or genetic. This mouse model bearing the non-mammalian
PP1 isoform in sperm should also be valuable in not only understanding the significance of the
presence of PP12 in all mammals but also in understanding the biochemical basis for fertility and
infertility in man.
