The Mg2+ transporter CNNM4 regulates sperm Ca2+ homeostasis and is essential for reproduction

Abstract

Ca2+ influx triggers sperm capacitation; however, the underlying regulatory mechanisms remain incompletely understood. Here, we show that CNNM4, a Mg 2+ transporter, is required for Ca 2+ influx during capacitation. We find that Cnnm4-deficient male mice are almost infertile because of sperm dysfunction. Motion analyses show that hyperactivation, a qualitative change in the mode of sperm motility during capacitation, is abrogated in Cnnm4-deficient sperm. In contrast, tyrosine phosphorylation of flagellar proteins, a hallmark of capacitation, is excessively augmented. These seemingly paradoxical phenotypes of Cnnm4-deficient sperm are very similar to those of sperm lacking a functional cation channel of sperm (CatSper) channel, which plays an essential role in Ca 2+ influx during sperm capacitation. Ca 2+ imaging analyses demonstrate that Ca 2+ influx is perturbed in Cnnm4-deficient sperm, and forced Ca 2+ entry into these sperm normalizes the level of tyrosine phosphorylation. Furthermore, we confirm the importance of CNNM4 in sperm by generating germcell-specific Cnnm4-deficient mice. These results suggest a new role of CNNM4 in sperm Ca 2+ homeostasis.

Genetic dissection of bull fertility in US Jersey dairy cattle

“…CNNM4 encodes a magnesium transporter that regulates calcium homeostasis during the sperm capacitation and is essential for ensuring sperm fertilizing ability (Yamazaki et al . ). Mutations in the DNAH1 gene, which encodes a member of the dynein family, cause multiple abnormalities of the sperm flagella, resulting in impaired sperm motility and, hence, male infertility (Ben Khelifa et al .…”

CrossTalk proposal: CNNM proteins are Na+/Mg2+ exchangers playing a central role in transepithelial Mg2+ (re)absorption

“…A similar increase of Mg levels was also observed in sperm isolated from Cnnm4 ‐deficient mice (Yamazaki et al . ). Moreover, inactivating mutations in Caenorhabditis elegans Cnnm orthologues, cnnm‐1 and cnnm‐3 , which are strongly expressed in the intestine, approximately doubled intestinal Mg levels (Ishii et al .…”

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

“…For example, mutations in CNNM2 or CNNM4 cause recessively inherited dominant hypomagnesemia and renal Mg 2+ wasting [2] or Jalili Syndrome, respectively [17][18][19][20][21][22][23]. Other disorders related to their altered activity include infertility [24,25], impaired brain development [26] along with neuropsychiatric disorders [27][28][29][30], and abnormal blood pressure levels [31]. On the other hand, CNNM3 and CNNM4 are involved in cancer progression [15,32] by associating with the highly oncogenic phosphatases of the regenerating liver (PRLs) and by promoting intracellular Mg 2+ accumulation that favors tumor growth and metastasis [6,[32][33][34].…”