Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Paul G Rack
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Zane J Hellmann
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Austen D Le
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Christopher M Adams
Stanford University Mass Spectrometry, Stanford University, Stanford, United States
Ryan D Leib
Stanford University Mass Spectrometry, Stanford University, Stanford, United States
Joshua E Elias
Chan Zuckerberg Biohub, Stanford University, Stanford, United States
John Perrino
Cell Science Imaging Facility, Stanford University School of Medicine, Stanford, United States
Barry Behr
Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, Stanford University School of Medicine, Stanford, United States
Yanfeng Li
Transgenic, Knockout, and Tumor Model Center, Stanford University School of Medicine, Stanford, United States
Jennifer Lin
Transgenic, Knockout, and Tumor Model Center, Stanford University School of Medicine, Stanford, United States
Hong Zeng
Transgenic, Knockout, and Tumor Model Center, Stanford University School of Medicine, Stanford, United States
James K Chen
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States; Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States; Department of Chemistry, Stanford University, Stanford, United States
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 Hipk4 knockout males are sterile, exhibiting phenotypes consistent with oligoasthenoteratozoospermia. Hipk4 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.