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PICK1 deficiency causes male infertility in mice by disrupting acrosome formation
Nan Xiao, … , Liwen Jiang, Jun Xia
Nan Xiao, … , Liwen Jiang, Jun Xia
Published March 2, 2009
Citation Information: J Clin Invest. 2009;119(4):802-812. https://doi.org/10.1172/JCI36230.
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Research Article Reproductive biology

PICK1 deficiency causes male infertility in mice by disrupting acrosome formation

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Abstract

Protein interacting with C kinase 1 (PICK1) is a peripheral membrane protein involved in protein trafficking, a function that has been well characterized in neurons. Here, we report that male mice deficient in PICK1 are infertile and have a phenotype resembling the human disease globozoospermia. The primary defect in the testes of Pick1-knockout mice was fragmentation of acrosomes in the early stages of spermiogenesis. This fragmentation was followed by defects in nuclear elongation and mitochondrial sheath formation, leading to round-headed sperm, reduced sperm count, and severely impaired sperm motility. We found that PICK1 interacted with Golgi-associated PDZ- and coiled-coil motif–containing protein (GOPC) and the primary catalytic subunit of protein kinase 2 (CK2α′), proteins whose deficiencies lead to globozoospermia in mice. PICK1 was highly expressed in round spermatids and localized to Golgi-derived proacrosomal granules. GOPC colocalized with PICK1 in the Golgi region and facilitated formation of PICK1-positive clusters. Furthermore, there was an increase in apoptosis in the seminiferous tubules of Pick1–/– mice, a phenotype also seen in CK2α′-deficient mice. Our results suggest that PICK1 is involved in vesicle trafficking from the Golgi apparatus to the acrosome and cooperates with other proteins such as GOPC and CK2α′ in acrosome biogenesis.

Authors

Nan Xiao, Chuen Kam, Chong Shen, Wenying Jin, Junqi Wang, Kwong Man Lee, Liwen Jiang, Jun Xia

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Figure 1

Decreased sperm number and abnormal sperm morphology in Pick1–/– mice.

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Decreased sperm number and abnormal sperm morphology in Pick1–/– mice.
 ...
(A) Total number of sperm from a single cauda epididymis: wild-type (Pick1+/+), 17.69 × 106 ± 1.62 × 106; Pick1+/–, 12.41 × 106 ± 1.10 × 106; Pick1–/–, 7.24 × 106 ± 0.81 × 106; mean ± SEM, n = 10, **P < 0.01. (B) Motile sperm number: Pick1+/+, 91.03 × 105 ± 15.5 × 105; Pick1+/–, 47.68 × 105 ± 9.32 × 105; Pick1–/–, 3.38 × 105 ± 1.21 × 105. (C) Linear motile sperm number: Pick1+/+, 58.80 × 105 ± 13.59 × 105; Pick1+/–, 22.13 × 105 ± 5.55 × 105; Pick1–/–, 0. (D) The percentage of globozoospermia-like sperm: Pick1+/+, 1.57% ± 0.81%; Pick1+/–, 2.26% ± 0.73%; Pick1–/–, 88.69% ± 9.57% (n = 3). (E) Morphology of unfixed sperm. Sperm from Pick1–/– mice lose the typical hook-shaped head of normal sperm; instead, they have round or irregular ball–like heads. In addition, defects in the tail can also be seen in sperm from Pick1–/– mice. (F) Immunostaining of acrosome matrix protein sp56 (red) and nucleus (nu, blue) in sperm. The acrosomes from Pick1–/– mice fail to acquire the crescent moon–shaped structure, are frequently fragmented, and are located in the wrong position. (G) Immunostaining of the mitochondrial sheath (ms, red) and nucleus in sperm. Mitochondrial sheaths in Pick–/– mice display various defects, including (left to right) abnormal sperm with aggregated mitochondrial sheaths, split mitochondrial sheaths, the mitochondrial sheath overlapping with the round nucleus, and the mitochondrial sheath wrapping around the round nucleus. Scale bars: 5 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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