A Testicular Germ Cell-Associated Serine-Threonine Kinase, MAK, Is Dispensable for Sperm Formation

Abstract

A member of the mitogen-activated protein kinase superfamily, MAK, has been proposed to have an important role in spermatogenesis, since Mak gene expression is highly restricted to testicular germ cells. To assess the biological function of MAK, we have established MAK-deficient (Mak ؊/؊ ) mice. Mak ؊/؊ mice developed normally, and no gross abnormalities were observed. Spermatogenesis of the Mak ؊/؊ mice was also intact, and most of the mice were fertile. However, Mak ؊/؊ male-derived litter sizes and their sperm motility in vitro were mildly reduced. These data show that function of MAK is not essential for spermatogenesis and male fertility. Spermatogenesis consists of three major stages: (i) a selfrenewing stage of spermatogonia (stem cells) by mitosis, (ii) a meiotic division stage of spermatocytes, and (iii) a morphological maturation stage during which haploid spermatids become mature spermatozoa. To understand the molecular mechanisms of mammalian spermatogenesis, research approaches using other cellular systems or experimental results from other species (for example, invertebrate systems) sometimes provide useful information. Since stem cells from other types of tissues also self renew and proliferate like spermatogonia, it is quite possible that similar mechanisms control the cellular events of both reproductive and other stem cells. Indeed, similar molecular properties have been described for different stem cell systems. For example, both steel factor and its receptor, c-kit, is crucial for hematopoiesis and spermatogenesis (9). Furthermore, hematopoietic stem cells and spermatogonial stem cells express integrin molecules on the cell surface and can be isolated based on expression of specific integrins (12,19,22). Meiosis is a process unique to the germ lineage cell; however, all eukaryotes undergo meiotic cell division in special circumstances. It has been shown that molecules critical for meiotic recombination in yeast also exist in mammals and have similar functions (reviewed in reference 6).Identification and characterization of specific molecules expressed within the testis is another approach to understanding spermatogenesis at a molecular level. Many testicular proteins have been identified and partially characterized (reviewed in reference 7). A serine-threonine kinase, MAK (male germ cell-associated kinase), is one such molecule. It was originally identified by weak cross-hybridization with a tyrosine kinase gene, v-ros (16). Since the expression of MAK protein was shown to be highly restricted in testicular germ cells at and after meiosis, it has been strongly speculated that MAK plays an important role(s) in cellular processes of spermatogenesis (10,13,16).To assess the function of MAK in spermatogenesis and male reproductive physiology, we generated Mak Ϫ/Ϫ mice by homologous recombination in embryonic stem (ES) cells and characterized their reproductive processes, including spermatogenesis and fertility. MATERIALS AND METHODS Establishment of Mak knockout ES cells and mice.A DNA fragment c...

Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase ( MAK ) as a cause of retinitis pigmentosa

“…Expression of Mak in rat was found to be strongest in meiotic spermatocytes, with down-regulation in postmeiotic spermatids (24). Despite its expression during the cell cycle in developing germ cells, targeted deletion of Mak in mice does not result in impaired fertility (25). Similarly, the majority of individuals with MAK-associated RP in our cohort each had two or more children (range = 0-4).…”

Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival

“…Mak-null mice were established previously, and it was reported that Mak is not essential for spermatogenesis, although Mak is highly expressed in the testis (17). To investigate in vivo Mak function in the retina, we analyzed this KO mouse.…”

“…We used Mak-KO mice with a deletion of exons 5-8 in the Mak genomic locus which encodes the catalytic kinase domain and the proline and glutamine-rich domain as previously reported (17). The Mak-KO mouse strain was provided by RIKEN BioResource Center through the National BioResource Project of the Japanese Government Ministry of Education, Culture, Sports, Science and Technology.…”

“…Mak was first identified as a gene highly expressed in testicular germ cells (16). Spermatogenesis of the Mak-KO mouse is intact (17). In addition to expression in the testis, Mak is also expressed in the retina (18,19).…”

Intestinal Cell Kinase (ICK) Promotes Activation of mTOR Complex 1 (mTORC1) through Phosphorylation of Raptor Thr-908

“…MAK is highly expressed in testis. However, the MAK-null mouse is viable and fertile, suggesting the existence of functional redundancy or compensation for the lack of MAK in testis (11). In the MAK-null retina, photoreceptors exhibit elongated cilia and progressive degeneration, suggesting that MAK is required for regulation of ciliary length and retinal photoreceptor survival (12).…”