Expression Profiling Reveals Developmentally Regulated lncRNA Repertoire in the Mouse Male Germline1

Bao, Jianqiang; Wu, Jingwen; Schuster, Andrew; Hennig, Grant W.; Yan, Wei

doi:10.1095/biolreprod.113.113308

Cited by 82 publications

(78 citation statements)

References 58 publications

(112 reference statements)

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“…Spata6 mRNA in situ hybridization in testis was performed as described previously (51). Details are provided in SI Appendix, Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Yuan

Stratton

Bao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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129

116

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"Pinhead sperm," or "acephalic sperm," a type of human teratozoospermia, refers to the condition in which ejaculate contains mostly sperm flagella without heads. Family clustering and homogeneity of this syndrome suggests a genetic basis, but the causative genes remain largely unknown. Here we report that Spata6, an evolutionarily conserved testis-specific gene, encodes a protein required for formation of the segmented columns and the capitulum, two major structures of the sperm connecting piece essential for linking the developing flagellum to the head during late spermiogenesis. Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Our proteomic analyses reveal that SPATA6 is involved in myosin-based microfilament transport through interaction with myosin subunits (e.g., MYL6).M ale gametes-spermatozoa-are produced in the testis through a process termed spermatogenesis, which can be divided into three phases: mitotic, meiotic, and haploid (1). In the mitotic phase, spermatogonial stem cells proliferate and differentiate into spermatogonia, which subsequently enter the meiotic phase and become spermatocytes. Spermatocytes undergo crossover, followed by two consecutive meiotic cell divisions to produce haploid spermatids. Spermatids then undergo a multistep differentiation process, also called spermiogenesis, to form spermatozoa. Severe disruptions in either the mitotic or the meiotic phase tend to cause azoospermia, whereas spermiogenic defects often lead to reduced sperm counts, aberrant sperm motility, and deformed spermatozoa, a condition termed oligoasthenoteratozoospermia (OAT) in humans (2, 3).OAT accounts for a significant proportion of male idiopathic infertility cases (2, 4). Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14). Extensive ultrastructral studies on humans and animals with acephalic spermatozoa suggest that this condition results from defects in formation of the connecting piece of spermatozoa during late spermiogenesis, including failure for the proximal centrioles to attach normally to the caudal portion of the sperm nuclei, leading to abnormal head-midpiece alignment, or a nuclear defect that interferes with formation of the implantation fossa, the normal lodging site for the sperm proximal centriole (16). Aberrant formation of the connecting piece leads to independent development of the sperm heads and flagella, and eventually these structures become separated within the seminiferous tubules or during their transition through the seminal tract as a consequence of increased instability of the head-midpiece junction (16,18)....

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“…Spata6 mRNA in situ hybridization in testis was performed as described previously (51). Details are provided in SI Appendix, Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Yuan

Stratton

Bao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

129

116

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“…Wu's group found lncRNA expression is correlated with epigenetic R136 A C-S Luk and others modification marks H3K4me3 and H3K27me3 (Sun et al 2013). Yan's group further showed by cross-link RNA IP experiment that 11 lncRNAs interact with one or multiple factors of chromatin-remodeling complexes, such as EZH2 and LSD1 (Bao et al 2013). Taken together, these data suggest that epigenetic regulation by lncRNAs may be involved in chromatin remodeling during spermatogenesis.…”

Section: Microarraysmentioning

confidence: 87%

“…Wu's group identified 8265 lncRNAs expressed in testis from either 6-day-or 8-week-old mouse, where 3025 showed difference in expression (Sun et al 2013). At the same time, Yan's group used a similar approach to investigate six time points in mouse testis development: embryonic day (E)12.5, E15.5, postnatal day 7 (PND 7), 14, 21, and adult (Bao et al 2013). They identified over 1000 down-and over 1500 up-regulated lncRNAs at each time point when compared with the previous time point.…”

Section: Microarraysmentioning

confidence: 99%

Long noncoding RNAs in spermatogenesis: insights from recent high-throughput transcriptome studies

Luk¹,

Chan²,

Rennert³

et al. 2014

Reproduction

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Spermatogenesis is a complex developmental process in which undifferentiated spermatogonia are differentiated into spermatocytes and spermatids through two rounds of meiotic division and finally giving rise to mature spermatozoa (sperm). These processes involve many testis-or male germ cell-specific gene products that undergo strict developmental regulations. As a result, identifying critical, regulatory genes controlling spermatogenesis provide the clues not only to the regulatory mechanism of spermatogenesis at the molecular level, but also to the identification of candidate genes for infertility or contraceptives development. Despite the biological importance in male germ cell development, the underlying mechanisms of stage-specific gene regulation and cellular transition during spermatogenesis remain largely elusive. Previous genomic studies on transcriptome profiling were largely limited to protein-coding genes. Importantly, protein-coding genes only account for a small percentage of transcriptome; the majority are noncoding transcripts that do not translate into proteins. Although small noncoding RNAs (ncRNAs) such as microRNAs, siRNAs, and Piwi-interacting RNAs are extensively investigated in male germ cell development, the role of long ncRNAs (lncRNAs), commonly defined as ncRNAs longer than 200 bp, is relatively unexplored. Herein, we summarize recent transcriptome studies on spermatogenesis and show examples that a subset of noncoding transcript population, known as lncRNAs, constitutes a novel regulatory target in spermatogenesis.

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“…RNA extraction and qPCR analyses were performed as previously described (Bao et al, 2013). All qPCR analyses were conducted using testicular samples in biological triplicate.…”

Section: Quantitative Real-time Pcr (Qpcr)mentioning

confidence: 99%

UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome

et al. 2015

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Nonsense-mediated mRNA decay (NMD) represents a highly conserved RNA surveillance mechanism through which mRNA transcripts bearing premature termination codons (PTCs) are selectively degraded to maintain transcriptomic fidelity in the cell. Numerous in vitro studies have demonstrated the importance of the NMD pathway; however, evidence supporting its physiological necessity has only just started to emerge. Here, we report that ablation of Upf2, which encodes a core NMD factor, in murine embryonic Sertoli cells (SCs) leads to severe testicular atrophy and male sterility owing to rapid depletion of both SCs and germ cells during prepubertal testicular development. RNA-Seq and bioinformatic analyses revealed impaired transcriptomic homeostasis in SC-specific Upf2 knockout testes, characterized by an accumulation of PTC-containing transcripts and the transcriptomewide dysregulation of genes encoding splicing factors and key proteins essential for SC fate control. Our data demonstrate an essential role of UPF2-mediated NMD in prepubertal SC development and male fertility.

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Expression Profiling Reveals Developmentally Regulated lncRNA Repertoire in the Mouse Male Germline1

Cited by 82 publications

References 58 publications

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Long noncoding RNAs in spermatogenesis: insights from recent high-throughput transcriptome studies

UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome

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