MEIG1 is essential for spermiogenesis in mice

Abstract

Spermatogenesis can be divided into three stages: spermatogonial mitosis, meiosis of spermatocytes, and spermiogenesis. During spermiogenesis, spermatids undergo dramatic morphological changes including formation of a flagellum and chromosomal packaging and condensation of the nucleus into the sperm head. The genes regulating the latter processes are largely unknown. We previously discovered that a bi-functional gene, Spag16, is essential for spermatogenesis. SPAG16S, the 35 kDa, testis-specific isoform derived from the Spag16 gene, was found to bind to meiosis expressed gene 1 product (MEIG1), a protein originally thought to play a role in meiosis. We inactivated the Meig1 gene and, unexpectedly, found that Meig1 mutant male mice had no obvious defect in meiosis, but were sterile as a result of impaired spermatogenesis at the stage of elongation and condensation. Transmission electron microscopy revealed that the manchette, a microtubular organelle essential for sperm head and flagellar formation was disrupted in spermatids of MEIG1-deficient mice. We also found that MEIG1 associates with the Parkin co-regulated gene (PACRG) protein, and that testicular PACRG protein is reduced in MEIG1-deficient mice. PACRG is thought to play a key role in assembly of the axonemes/flagella and the reproductive phenotype of Pacrg-deficient mice mirrors that of the Meig1 mutant mice. Our findings reveal a critical role for the MEIG1/PARCG partnership in manchette structure and function and the control of spermiogenesis. Spermatogenesis can be divided into three stages: spermatogonial mitosis, meiosis of spermatocytes, and spermiogenesis, the final step of spermatogenesis. During this stage, the haploid round spermatids differentiate into species-specific shaped spermatozoon, with dramatic morphological changes, including elongation and condensation of the nucleus, and formation of the flagellum (1, 2). Even though some genes have been reported to be indispensable for this process (3, 4), the underlying mechanisms remains largely unknown and need to be elucidated.Mouse meiosis expressed gene 1 (Meig1) was originally identified in a search for mammalian genes potentially involved in meiosis. Two Meig1 transcripts, 11a2 and 2a2, were identified previously, both containing three exons. The two transcripts share the same ORF and 3Ј UTR, but differ in their 5Ј UTRs. Each has a unique non-translated exon 1. The 11a2 message was expressed in somatic cells in the testis, including Leydig cells, whereas the predominant 2a2 isoform was reported to be germ cell-specific. The 2a2 transcript begins to accumulate in the testis at day (d)8-9 of postnatal (pn) development, coinciding with the entry of germ cells into meiosis, and is expressed most abundantly at pn d14 and subsequent stages, when spermatocytes enter the pachytene stage. In situ hybridization analysis showed that Meig1 expression level was low in leptotene cells and increased as the cells progressed through zygotene and pachytene stages. In addition, Meig1 message was also detecte...

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“…The stage of elongation and condensation of spermatogenesis was shown to be significantly impaired. 11 Salzberg et al 12 obtained similar results showing that developing germ cells rarely differentiated past the spermatogenesis stage in their Meig1 À/ À male mice; the few sperms that managed to reach the epididymis were totally immotile. These consistent findings indicated that the murine Meig1 gene was crucial for spermatogenesis in mice.…”

“…11,12 Meig1 is a murine gene with testis-specific expression. Zhang et al 11 found that homozygous Meig1-knockout male mice are viable but sterile, whereas no obvious defect was detected in heterozygous Meig1-knockout mice. The stage of elongation and condensation of spermatogenesis was shown to be significantly impaired.…”

Mouse models in male fertility research

“…Several mouse models, and microscopic studies, strongly suggest that these structures are integral to the formation of normal sperm head shape. [99][100][101] Data also suggest that the manchette is involved in the transport of proteins required for sperm tail formation in a process known as intramanchette transport. [100][101][102] Mouse models have also been critically important in defining the mechanisms of sperm tail formation and have revealed some surprising phenomena and the etiology of several significant human pathologies.…”

“…[99][100][101] Data also suggest that the manchette is involved in the transport of proteins required for sperm tail formation in a process known as intramanchette transport. [100][101][102] Mouse models have also been critically important in defining the mechanisms of sperm tail formation and have revealed some surprising phenomena and the etiology of several significant human pathologies. 52 During the last few years in particular, research has begun to illustrate the importance of axoneme function, not only for sperm motility but also for cilia function in a range of somatic tissues and many aspects of human health.…”

Sperm dysfunction and ciliopathy

“…In mice, PACRG is associated with MEIG1, which was identified as a binding partner of a CP protein SPAG16 (PF20) [175]. MEIG1-knockout mice show male infertility, but no other phenotypes for ciliopathy are observed [176][177][178]. Further studies suggest that MEIG1/PACRG plays a critical role in the control of the structure called ''manchette'' [179], a microtubule-based structure transiently formed during spermiogenesis.…”