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 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.
Highlights
Spermiogenesis is a critical, post-meiotic phase of male gametogenesis defined by the differentiation of spermatids into spermatozoa (Figure 1A–B; Russell et al, 1990)
Gene expression data available through the Genotype Tissue Expression Project and the Mammalian Reproductive Genetics Database indicate that homeodomaininteracting protein kinase 4 (HIPK4) is largely expressed in the testis, with lower levels detected in the brain
The population of Hipk4-positive spermatids expanded until 29 dpp, at which point Hipk4 mRNA became undetectable in elongating spermatids circumscribing the seminiferous lumen
Summary
Spermiogenesis is a critical, post-meiotic phase of male gametogenesis defined by the differentiation of spermatids into spermatozoa (Figure 1A–B; Russell et al, 1990). This dramatic morphological transformation is mediated by a series of cytological processes that are unique to the testis (Kierszenbaum et al, 2007; O’Donnell, 2014). Golgi-derived vesicles give rise to the acrosome (Berruti and Paiardi, 2011), a cap-like structure that is anchored to the anterior nuclear membrane by a filamentous actin (F-actin)- and keratin 5-containing plate called the acroplaxome (Kierszenbaum et al, 2003a; Kierszenbaum et al, 2004).
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