HIPK4 is Essential for Murine Spermiogenesis

Overview

Journal Elife

Specialty Biology

Date 2020 Mar 13

PMID 32163033

Citations 31

Authors

J Aaron Crapster

Paul G Rack

Zane J Hellmann

Austen D Le

Christopher M Adams

Ryan D Leib

Joshua E Elias

John Perrino

Barry Behr

Yanfeng Li

Jennifer Lin

Hong Zeng

James K Chen

Affiliations

Soon will be listed here.

Abstract

Mammalian spermiogenesis is a remarkable cellular transformation, during which round spermatids elongate into chromatin-condensed spermatozoa. The signaling pathways that coordinate this process are not well understood, and we demonstrate here that homeodomain-interacting protein kinase 4 (HIPK4) is essential for spermiogenesis and male fertility in mice. HIPK4 is predominantly expressed in round and early elongating spermatids, and knockout males are sterile, exhibiting phenotypes consistent with oligoasthenoteratozoospermia. mutant sperm have reduced oocyte binding and are incompetent for in vitro fertilization, but they can still produce viable offspring via intracytoplasmic sperm injection. Optical and electron microscopy of HIPK4-null male germ cells reveals defects in the filamentous actin (F-actin)-scaffolded acroplaxome during spermatid elongation and abnormal head morphologies in mature spermatozoa. We further observe that HIPK4 overexpression induces branched F-actin structures in cultured fibroblasts and that HIPK4 deficiency alters the subcellular distribution of an F-actin capping protein in the testis, supporting a role for this kinase in cytoskeleton remodeling. Our findings establish HIPK4 as an essential regulator of sperm head shaping and potential target for male contraception.

Citing Articles

Fam170a deficiency causes male infertility by impairing histone-to-protamine exchange during mouse spermiogenesis.

Cheng J, Gu Y, Wang Y, Xun J, Wang G, Wang Y Nucleic Acids Res. 2025; 53(3).

PMID: 39868537 PMC: 11760970. DOI: 10.1093/nar/gkaf023.

Autophagy modulates Arabidopsis male gametophyte fertility and controls actin organization.

Yan H, Lu Z, Du X, You Z, Yang M, Li N Nat Commun. 2024; 15(1):10071.

PMID: 39567510 PMC: 11579482. DOI: 10.1038/s41467-024-54468-8.

RNA helicase D1PAS1 resolves R-loops and forms a complex for mouse pachytene piRNA biogenesis required for male fertility.

Choi H, Zhou L, Zhao Y, Dean J Nucleic Acids Res. 2024; 52(19):11973-11994.

PMID: 39162228 PMC: 11514495. DOI: 10.1093/nar/gkae712.

The uniqueness of on-demand male contraception.

Rivera Sanchez N, Ritagliati C, Kopf G, Kretschmer S, Buck J, Levin L Mol Aspects Med. 2024; 97:101281.

PMID: 38805792 PMC: 11167369. DOI: 10.1016/j.mam.2024.101281.

Oxidative Stress Biomarkers in Male Infertility: Established Methodologies and Future Perspectives.

Mottola F, Palmieri I, Carannante M, Barretta A, Roychoudhury S, Rocco L Genes (Basel). 2024; 15(5).

PMID: 38790168 PMC: 11121722. DOI: 10.3390/genes15050539.

References

Kueng P, Nikolova Z, Djonov V, Hemphill A, Rohrbach V, Boehlen D . A novel family of serine/threonine kinases participating in spermiogenesis. J Cell Biol. 1998; 139(7):1851-9. PMC: 2132653. DOI: 10.1083/jcb.139.7.1851. View

Yao R, Ito C, Natsume Y, Sugitani Y, Yamanaka H, Kuretake S . Lack of acrosome formation in mice lacking a Golgi protein, GOPC. Proc Natl Acad Sci U S A. 2002; 99(17):11211-6. PMC: 123235. DOI: 10.1073/pnas.162027899. View

Nozawa Y, Yao E, Gacayan R, Xu S, Chuang P . Mammalian Fused is essential for sperm head shaping and periaxonemal structure formation during spermatogenesis. Dev Biol. 2014; 388(2):170-80. PMC: 3982599. DOI: 10.1016/j.ydbio.2014.02.002. View

Green C, Ma Q, Manske G, Shami A, Zheng X, Marini S . A Comprehensive Roadmap of Murine Spermatogenesis Defined by Single-Cell RNA-Seq. Dev Cell. 2018; 46(5):651-667.e10. PMC: 6713459. DOI: 10.1016/j.devcel.2018.07.025. View

Litovchick L, Florens L, Swanson S, Washburn M, DeCaprio J . DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 2011; 25(8):801-13. PMC: 3078706. DOI: 10.1101/gad.2034211. View

Geyer C, Inselman A, Sunman J, Bornstein S, Handel M, Eddy E . A missense mutation in the Capza3 gene and disruption of F-actin organization in spermatids of repro32 infertile male mice. Dev Biol. 2009; 330(1):142-52. PMC: 2688473. DOI: 10.1016/j.ydbio.2009.03.020. View

Aaron Crapster J, Rack P, Hellmann Z, Le A, Adams C, Leib R . HIPK4 is essential for murine spermiogenesis. Elife. 2020; 9. PMC: 7067585. DOI: 10.7554/eLife.50209. View

Craig A, Zirngibl R, Williams K, Cole L, Greer P . Mice devoid of fer protein-tyrosine kinase activity are viable and fertile but display reduced cortactin phosphorylation. Mol Cell Biol. 2001; 21(2):603-13. PMC: 86629. DOI: 10.1128/MCB.21.2.603-613.2001. View

Austin C . Observations on the penetration of the sperm in the mammalian egg. Aust J Sci Res B. 1951; 4(4):581-96. DOI: 10.1071/bi9510581. View

10.

Zhou J, Du Y, Qin W, Hu Y, Huang Y, Bao L . RIM-BP3 is a manchette-associated protein essential for spermiogenesis. Development. 2008; 136(3):373-82. DOI: 10.1242/dev.030858. View

11.

Oko R, Moussakova L, Clermont Y . Regional differences in composition of the perforatorium and outer periacrosomal layer of the rat spermatozoon as revealed by immunocytochemistry. Am J Anat. 1990; 188(1):64-73. DOI: 10.1002/aja.1001880108. View

12.

Arai S, Matsushita A, Du K, Yagi K, Okazaki Y, Kurokawa R . Novel homeodomain-interacting protein kinase family member, HIPK4, phosphorylates human p53 at serine 9. FEBS Lett. 2007; 581(29):5649-57. DOI: 10.1016/j.febslet.2007.11.022. View

13.

Fujihara Y, Satouh Y, Inoue N, Isotani A, Ikawa M, Okabe M . SPACA1-deficient male mice are infertile with abnormally shaped sperm heads reminiscent of globozoospermia. Development. 2012; 139(19):3583-9. DOI: 10.1242/dev.081778. View

14.

ORand M . Modification of the sperm membrane during capacitation. Ann N Y Acad Sci. 1982; 383:392-404. DOI: 10.1111/j.1749-6632.1982.tb23180.x. View

15.

Keshet E, Itin A, Fischman K, Nir U . The testis-specific transcript (ferT) of the tyrosine kinase FER is expressed during spermatogenesis in a stage-specific manner. Mol Cell Biol. 1990; 10(9):5021-5. PMC: 361143. DOI: 10.1128/mcb.10.9.5021-5025.1990. View

16.

Kierszenbaum A, Tres L . The acrosome-acroplaxome-manchette complex and the shaping of the spermatid head. Arch Histol Cytol. 2005; 67(4):271-84. DOI: 10.1679/aohc.67.271. View

17.

Tuttelmann F, Ruckert C, Ropke A . Disorders of spermatogenesis: Perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med Genet. 2018; 30(1):12-20. PMC: 5838132. DOI: 10.1007/s11825-018-0181-7. View

18.

Gob E, Schmitt J, Benavente R, Alsheimer M . Mammalian sperm head formation involves different polarization of two novel LINC complexes. PLoS One. 2010; 5(8):e12072. PMC: 2919408. DOI: 10.1371/journal.pone.0012072. View

19.

Spiridonov N, Wong L, Zerfas P, Starost M, Pack S, Paweletz C . Identification and characterization of SSTK, a serine/threonine protein kinase essential for male fertility. Mol Cell Biol. 2005; 25(10):4250-61. PMC: 1087724. DOI: 10.1128/MCB.25.10.4250-4261.2005. View

20.

Di Vona C, Bezdan D, Islam A, Salichs E, Lopez-Bigas N, Ossowski S . Chromatin-wide profiling of DYRK1A reveals a role as a gene-specific RNA polymerase II CTD kinase. Mol Cell. 2015; 57(3):506-20. DOI: 10.1016/j.molcel.2014.12.026. View