Deficiency of Mkrn2 causes abnormal spermiogenesis and spermiation, and impairs male fertility

Abstract

Although recent studies have shed insights on some of the potential causes of male infertility, new underlining molecular mechanisms still remain to be elucidated. Makorin-2 (Mkrn2) is an evolutionarily conserved gene whose biological functions are not fully known. We developed an Mrkn2 knockout mouse model to study the role of this gene, and found that deletion of Mkrn2 in mice led to male infertility. Mkrn2 knockout mice produced abnormal sperms characterized by low number, poor motility, and aberrant morphology. Disruption of Mkrn2 also caused failure of sperm release (spermiation failure) and misarrangement of ectoplasmic specialization (ES) in testes, thus impairing spermiogenesis and spermiation. To understand the molecular mechanism, we found that expression of Odf2, a vital protein in spermatogenesis, was significantly decreased. In addition, we found that expression levels of Odf2 were decreased in Mkrn2 knockout mice. We also found that MKRN2 was prominently expressed in the sperm of normal men, but was significantly reduced in infertile men. This result indicates that our finding is clinically relevant. The results of our study provided insights into a new mechanism of male infertility caused by the MKRN2 downregulation.

Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation

“…Since in vertebrates MKRN genes are highly expressed in gonads and early embryos as well, it is possible that similar molecular mechanisms are employed to regulate gene expression at these stages [33]. Consistent with this, MKRN2 was recently found to be essential for male fertility in mice [58]. Thus, our study provides a mechanism that explains the role of Mkrn1 in translation and constitutes a solid framework for future investigations deciphering the roles of vertebrate MKRNs in post-transcriptional control of gene expression during gametogenesis and early development.…”

Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression ofoskartranslation

“…Since in vertebrates MKRN genes are also highly expressed in gonads and early embryos, it is possible that similar molecular mechanisms are employed to regulate gene expression at these stages (Bohne et al, 2010). Along these lines, MKRN2 was found recently to be essential for male fertility in mice (Qian et al, 2016). Thus, our study provides a solid framework for future investigations deciphering the role of vertebrates MKRN in posttranscriptional control of gene expression during gametogenesis and early development.…”

Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions

“…59 Interestingly, studies using a Mkrn2 knockout (KO) mouse model reported a role of Mkrn2 in male fertility. 56 While male and female Mkrn2 KO animals were viable with no apparent developmental abnormalities, the mutant animals showed a decrease in body weight. Female Mkrn2 KO mice were fertile but had a reduction in their fertility rate.…”

“…45 In adult mice, Mkrn2 mRNA and protein were ubiquitously expressed at low levels in various tissues (brain, thymus, heart, lung, liver, spleen, kidney, ovary, uterus, and seminal vesicle) with more specific, high expression in the testis. 56 The first study to investigate Mkrn2 function reported that, in Xenopus, Mkrn2 played a negative role in neurogenesis via PI3K/Akt signaling and was essential for proper embryonic neural development. 57 The third C3H zinc finger, Cys-His motif, and C3HC4 RING zinc finger domains were indispensable for this inhibitory effect of Mkrn2 on neurogenesis.…”

“…In addition, human MKRN2 expression levels were significantly decreased in the sperm of patients with oligoasthenoteratozoospermia, the most common cause of subfertility in men, compared with a control group of fertile men, revealing a correlation between MKRN2 expression and human male infertility. 56 Any potential role of Mkrn2 in pubertal development remains to be elucidated.…”