HIPK4 is essential for murine spermiogenesis

Crapster, J. Aaron; Rack, Paul G.; Hellmann, Zane J.; Le, Austen D; Adams, Christopher M.; Leib, Ryan D.; Elias, Joshua E.; Perrino, John; Behr, Barry; Li, Yanfeng; Lin, Jennifer S; Zeng, Hong; Chen, James

doi:10.7554/elife.50209

Cited by 44 publications

(45 citation statements)

References 82 publications

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“…Interestingly, HIPK4, a member of the homeodomain-interacting protein kinase (HIPK) subfamily, is predominantly expressed in the testis and has been shown to play a role in spermatogenesis. HIPK4 is a dual-specificity kinase with a restricted localization to round and early elongating spermatids in mouse testis; localization in human testis tissue has also been confirmed [ 21 ]. HIPK4 knockout mice are infertile in vivo and by in vitro fertilization (IVF), although they can produce viable progeny by intracytoplasmic sperm injection (ICSI).…”

Section: Introductionmentioning

confidence: 99%

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Salicioni

Gervasi

Sosnik

et al. 2020

Biology of Reproduction

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Male contraception is a very active area of research. Several hormonal agents have entered clinical trials, while potential non-hormonal targets have been brought to light more recently and are at earlier stages of development. The general strategy is to target genes along the molecular pathways of sperm production, maturation, or function, and it is predicted that these novel approaches will hopefully lead to more selective male contraceptive compounds with a decreased side effect burden. Protein kinases are known to play a major role in signaling events associated with sperm differentiation and function. In this review, we focus our analysis on the testis-specific serine kinase (TSSK) protein family. We have previously shown that members of the family of TSSKs are postmeiotically expressed in male germ cells and in mature mammalian sperm. The restricted postmeiotic expression of TSSKs as well as the importance of phosphorylation in signaling processes strongly suggests that TSSKs have an important role in germ cell differentiation and/or sperm function. This prediction has been supported by the reported sterile phenotype of the Tssk6 knockout (KO) mice and of the double Tssk1 and Tssk2 KO mice and by the male subfertile phenotype observed in a Tssk4 KO mouse model. Summary Sentence The established role of TSSKs in spermiogenesis and in male fertility, together with their unique kinase features, strongly supports this family of protein kinases as a very promising drug discovery target for development of a non-hormonal male contraceptive.

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Section: Introductionmentioning

confidence: 99%

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Salicioni

Gervasi

Sosnik

et al. 2020

Biology of Reproduction

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show abstract

“…If not, this protein could be localized elsewhere but have an indirect action via a regulatory role. Such a phenotype has already been observed in Hipk4 (homeodomain-interacting protein kinase 4) KO mice demonstrating that this gene is essential for murine spermiogenesis as a regulator of the shape of the sperm head [ 22 ], or in germ cell-specific Sirt1 KO infertile mice where disrupted spermiogenesis caused defects in acrosome biogenesis, which resulted in a phenotype similar to that observed in human globozoospermia [ 23 ]. In addition, the absence of DPY19L2, an inner nuclear membrane protein, causes globozoospermia in human and in mice by preventing the anchoring of the acrosome to the nucleus [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 87%

Identification of a New QTL Region on Mouse Chromosome 1 Responsible for Male Hypofertility: Phenotype Characterization and Candidate Genes

Vatin

Girault

Firlej

et al. 2020

IJMS

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Male fertility disorders often have their origin in disturbed spermatogenesis, which can be induced by genetic factors. In this study, we used interspecific recombinant congenic mouse strains (IRCS) to identify genes responsible for male infertility. Using ultrasonography, in vivo and in vitro fertilization (IVF) and electron microscopy, the phenotyping of several IRCS carrying mouse chromosome 1 segments of Mus spretus origin revealed a decrease in the ability of sperm to fertilize. This teratozoospermia included the abnormal anchoring of the acrosome to the nucleus and a persistence of residual bodies at the level of epididymal sperm midpiece. We identified a quantitative trait locus (QTL) responsible for these phenotypes and we have proposed a short list of candidate genes specifically expressed in spermatids. The future functional validation of candidate genes should allow the identification of new genes and mechanisms involved in male infertility.

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“…That is the case of HRB , a gene that is essential for acrosome formation with deficient mice showing meiosis and spermiogenesis defects leading to abnormal sperm and infertility. 51 , 52 HIPK4 , which is associated to abnormal round-headed spermatozoa 53 and CFAP100 , 54 KIF24 , 55 HAP1 54 and MARCH10 , 56 all linked to ciliogenesis. Other genes within this group were related to sperm maturation in the epididymis with impact on sperm motility, acrosome formation, mitochondria homeostasis or capacitation, such as KCNK17 , 57 PLA2G3 , 58 PPP3CC , 59 SLC26A8 , 60 CCDC189 61 and PINK1 .…”

Section: Resultsmentioning

confidence: 99%

Whole genome sequencing identifies allelic ratio distortion in sperm involving genes related to spermatogenesis in a swine model

et al. 2020

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Transmission Ratio Distortion (TRD), the uneven transmission of an allele from a parent to its offspring, can be caused by allelic differences affecting gametogenesis, fertilization or embryogenesis. However, TRD remains vaguely studied at a genomic scale. We sequenced the diploid and haploid genomes of 3 boars from leukocytes and spermatozoa at 50x to shed light into the genetic basis of spermatogenesis-caused Allelic Ratio Distortion (ARD). We first developed a binomial model to identify ARD by simultaneously analysing all three males. This led to the identification of 55 ARD SNPs, most of which were animal-specific. We then evaluated ARD individually within each pig by a Fisher Exact Test and identified 2 shared genes (TOP3A and UNC5B) and 4 shared genomic regions harbouring distinct ARD SNPs in the 3 boars. The shared genomic regions contained candidate genes with functions related to spermatogenesis including AK7, ARID4B, BDKRB2, GSK3B, NID1, NSMCE1, PALB2, VRK1 and ZC3H13. Using the Fisher Test, we also identified 378 genes containing variants with protein damaging potential in at least one boar, a high proportion of which, including FAM120B, TDRD15, JAM2 or AOX4 among others, are associated to spermatogenesis. Overall, our results show that sperm is subjected to ARD with variants associated to a wide variety of genes involved in different stages of spermatogenesis.

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HIPK4 is essential for murine spermiogenesis

Cited by 44 publications

References 82 publications

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Identification of a New QTL Region on Mouse Chromosome 1 Responsible for Male Hypofertility: Phenotype Characterization and Candidate Genes

Whole genome sequencing identifies allelic ratio distortion in sperm involving genes related to spermatogenesis in a swine model

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