The Expression Level of Septin12 Is Critical for Spermiogenesis

• Published in: The American journal of pathology Vol. 174; no. 5; pp. 1857 - 1868
• Main Authors: Lin, Ying-Hung, Lin, Yung-Ming, Wang, Ya-Yun, Yu, I-Shing, Lin, Yi-Wen, Wang, Yun-Han, Wu, Ching-Ming, Pan, Hsien-An, Chao, Shin-Chih, Yen, Pauline H, Lin, Shu-Wha, Kuo, Pao-Lin
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.05.2009; ASIP; American Society for Investigative Pathology
• Subjects: Acrosome - metabolism; Animals; Apoptosis - physiology; Asthenozoospermia - metabolism; Biological and medical sciences; Blotting, Western; Cell Differentiation; Embryonic Stem Cells - metabolism; Fluorescent Antibody Technique; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; Infertility, Male - metabolism; Infertility, Male - pathology; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Meiosis - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Peptide Fragments - immunology; Peptide Fragments - metabolism; Phenotype; Rabbits; Rats; Regular; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Semen Analysis; Septins; Spermatids - metabolism; Spermatogenesis - physiology; Spermatozoa - metabolism; Testis - cytology; Testis - metabolism; Anatomic pathology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080955

Septins belong to a family of polymerizing GTP-binding proteins that are required for many cellular functions, such as membrane compartmentalization, vesicular trafficking, mitosis, and cytoskeletal remodeling. One family member, septin12, is expressed specifically in the testis. In this study, we found septin12 expressed in multiple subcellular compartments during terminal differentiation of mouse germ cells. In humans, the testicular tissues of men with either hypospermatogenesis or maturation arrest had lower levels of SEPTIN12 transcripts than normal men. In addition, increased numbers of spermatozoa with abnormal head, neck, and tail morphologies lacked SEPT12 immunostaining signals, as compared with normal spermatozoa. To elucidate the role of septin12, we generated 129 embryonic stem cells containing a septin12 mutant allele with a deletion in the exons that encode the N-terminal GTP-binding domain. Most chimeras derived from the targeted embryonic stem cells were infertile, and the few fertile chimeras only produced offspring with a C57BL/6 background. Semen analysis of the infertile chimeras showed a decreased sperm count, decreased sperm motility, and spermatozoa with defects involving all subcellular compartments. The testicular phenotypes included maturation arrest of germ cells at the spermatid stage, sloughing of round spermatids, and increased apoptosis of germ cells. Electron microscopic examination of spermatozoa showed misshapen nuclei, disorganized mitochondria, and broken acrosomes. Our data indicate that Septin12 expression levels are critical for mammalian spermiogenesis.