Sperm

The sperm cell, or spermatozoon, is the male motile gamete of humans and animals. It was first described in 1677 by van Leeuwenhoek. In contrast to other cell types, spermatozoa lacks most of the standard organelles, such as the endoplasmic reticulum and the Golgi apparatus. During spermatogenesis, stem cells in the testis develop into a highly specialized haploid cell type that is optimized for swimming to, penetrating, and ultimately fusing with the female gamete, known as the oocyte, to form a diploid and totipotent zygote. To achieve this, sperm cells contain several unique subcellular structures, including a long motile cilium called the flagellum, allowing high motility and aiding egg penetration, and a sac containing enzymes used for penetrating the egg, called the acrosome. Examples of proteins localizing to different regions of spermatozoa can be seen in Figure 1.

In the subcellular resource, 645 genes (3% of all human protein-coding genes) have been shown to encode proteins that localize to human spermatozoa and their unique sub-compartments (Figure 2). There are also 65 genes encoding proteins that have been found to loalize to mitochondria in sperm. A Gene Ontology (GO)-based functional enrichment analysis of genes encoding proteins in the sperm-specific substructures shows an enrichment of genes associated with biological processes related to sperm motility, organization and assembly of the cilium, spermatogenesis, and microtubule-based transport. Approximately 76% (n=493) of the proteins that localize to the sperm cell can also be detected in additional cellular compartments in other cell types, with the most common additional localization being mitochondria.

SPACA1 - Sperm
DYDC1 - Sperm
ARMC12 - Sperm

Figure 1. Examples of proteins localized to the sperm cell and some of its substructures. SPACA1 is a key protein for establishing a normal morphology during spermatogenesis and plays a role in the formation of the acrosome vesicle. DYDC1 localizes along the length of the entire flagellum and is important for sperm motility. ARMC12 is a sperm mitochondrial protein that is essential for male fertility and for the formation of the mitochondrial sheath in the mid piece of sperm cells.

Figure 2. 3% of all human protein-coding genes encode proteins that have been shown to localize to the sperm cell and its substructures. Each bar is clickable and gives a search result of proteins that belong to the selected category.

The structure of the sperm cell

Substructures

• Acrosome: 133
• Equatorial segment: 81
• Perinuclear theca: 68
• Calyx: 70
• Connecting piece: 93
• Flagellar centriole: 115
• Mid piece: 350
• Principal piece: 387
• End piece: 194
• Annulus: 50

The sperm cell is a highly specialized cell type with a distinct morphology compared to other cell types. During spermatogenesis, stem cells in testis undergo several steps of morphological and functional remodeling, leading to the formation of a haploid cell, consisting of a head region with species-specific morphology connected to a long tail (Schneider S et al. (2023)).

The head region of sperm contains the nucleus, the acrosome, the equatorial segment, and the perinuclear theca, including the calyx. The nucleus contains the haploid paternal genome, with one copy of each chromosome, as well as a multitude of different RNA molecules. The DNA in the nucleus of the sperm head is hypercondensed into a genetically inactive state, with protamines substituting the core histones. The acrosome covers the anterior portion of the sperm head and is derived from the Golgi apparatus as well as the plasma membrane of sperm progenitor cells. It contains different digestive enzymes and other molecules that are exocytosed during the acrosome reaction, which occurs when the sperm cell touches the egg coat and which is essential to enable penetration and fertilization. The equatorial segment is a region in the middle portion of the sperm head that contains a unique set of proteins, which seem to play a role in plasmamembrane fusion between the spermatozoon and the oocyte. The condensed cytosolic regions, or perinuclear theca, of the sperm head can been divided into a subacrosomal and postacrosomal part. The subacrosomal part, referred to as the perinuclear theca in the sucelluar resource, develops early during spermatogenesis and is a thin cytosolic layer between the acrosome vesicle and nuclear envelope, which is continuous with the outer periacrosomal layer. This region is important for acrosome assebly. The postacrosomal part, known as the calyx, is localized between the nuclear envelope and the sperm plasma membrane. It consists of cytosolic proteins that are transported via the sperm manchette and is formed during the maturation phase when the sperm head is elongated, and is important for sperm–egg interactions and egg activation during fertilization (Balhorn R. (2007); Khawar MB et al. (2019); Schneider S et al. (2023)). Examples of proteins localizing to the sperm head regions can be seen in Figure 3.

SPACA3 - Acrosome
SPESP1 - Equatorial segment

RAP1GAP2 - Perinuclear theca
CYLC2 - Calyx

Figure 3. Examples showing the different sperm head substructures and staining patterns. SPACA3 is localized to the acrosome and is thought to be involved in the sperm-egg fusion event during fertilization. SPESP1 is localized to the equatorial segment and is important for the fertilization ability of the sperm cell. RAP1GAP2 is localized to the perinuclear theca and is involed in the acrosome reaction. CYLC2 is localized to the calyx and is a testis-specific protein important for proper assembly of the calyx during spermatogenesis.

Between the head and the tail of spermatozoa is the connecting piece (neck region). It contains the two flagellar centrioles; one typical barrel-shaped proximal centriole and one atypical distal centriole, which is subject to compositional and structural remodelling during spermatogenesis Fishman EL et al. (2018). The proximal centriole is important for the connection to the sperm head and the nucleus. The distal centriole is connected to the tail, also known as the flagellum. The flagellum is about 10 times (55 μm) longer than the sperm head and divided into three structurally distinct parts: the mid piece, the principal piece, and the end piece. Common for all three parts is the microtubule-based axoneme that runs along the entire length of the flagellum. As for other motile cilia, the microtubules of the axoneme form a central pair surrounded by a ring of nine peripheral doublet microtubules linked by nexin and radial spokes, creating the characteristic "9+2" structure. The peripheral doublet microtubules are further supported by inner and outer dynein arms, which consist of motor proteins that help create the bending motion of the flagellum. In the mid piece and principal piece, the axoneme is surrounded by outer dense fibers that protect the cells from shear forces during movement. In the principal piece, two of the ODFs are replaced by the longitudinal columns of the fibrous sheat. The fibrous sheet protects and supports the axoneme, but also has a role in providing energy for flagellar motility though glycolysis. Sperm motility is mainly powered by ATP generated by a large number of mitochondria located in the mitochondrial sheath that coils around the axoneme of the mid piece (Dai C et al. (2021); Wang J et al. (2022); Dirami T et al. (2015)). In vertebrates, a spetin-based ring-shaped structure called the annulus can be found between the mid piece and the principal piece. The annulus has been hypothesized to act as a diffusion barrier of proteins, guiding flagellar growth along the axoneme and the alignment of mitochondria in the mid piece. The end piece acks the fibrous sheet, and simply consist of the axoneme wrapped by the plasma membrane. In the most distal segment, the 9+2 doublet symmetry of the axoneme is lost, an the microtubules form singlets. The end piece is where the flagellum can grow and shrink, and it thus plays an important role in coordinating growth and intra‐flagellar transport. Examples of proteins localizing to the substructures of the neck and tail can be seen in Figure 4.

CATIP - Connecting piece
WDPCP - Flagellar centriole
RSPH1 - Mid piece
GAPDHS - Principal piece
DNAH2 - End piece
SEPTIN4 - Annulus

Figure 4. Examples showing the different sperm neck region and flagellar substructures and staining pattern CATIP is localized to the connecting piece and modulates actin polymerization. WDPCP is localized to the flagellar centriole and is a part of the CPLANE (ciliogenesis and planar polarity effectors) complex that is involved in the recruitment of interflagellar transport proteins to the basal body of cilia. RSPH1 is localized to the mid piece of the flagellum and is part of the radial spoke complex and is important for the motility of sperm. GAPDHS is localized to the principal piece of the flagellum and is a testis-specific enzyme that regulates the switch between different pathways for energy production in the sperm. DNAH2 is localized to the end piece of the flagellum and is a part of the inner dynein arm complex. SEPTIN4 is localized to the annulus where it is essential for its formation.

A selection of proteins suitable as markers for the sperm cell and its substructures can be found in Table 1.

Table 1. Selection of proteins suitable as markers for the sperm cell and its substructures.

The function of the sperm cell and its substructures

The main function of the sperm cell is to carry the male genetic information to the oocyte during fertilization. Once the sperm cells are produced, they reside in an immature state in the testis. Upon ejaculation, sperm mature within the female reproductive tract. This maturation process is triggered by exposure to environmental cues, such as bicarbonate concentration, and leads to a more progressive flagellar beat and the capability to penetrate the egg vestments. The flagellum is used as the sperm cell's motor, rudder, and sensor, powered by the ATP produced by mitochondria in the mid piece. Flagellar movement results from the sliding of the axonemal microtubules under the action of dynein arms.

Multiple sensory proteins on the flagellar membrane, such as ion channels, detect signals and initiate a downstream signaling cascade that orchestrates the flagellar beat to modulate the swimming path (Alvarez L et al. (2014)).The sperm cell utilizes physical and chemical environmental cues, such as chemotaxis, haptotaxis, thermotaxis, or rheotaxis to navigate to the oocyte (Wachten D et al. (2017)). As sperm progress through the female reproductive tract and approach the egg, changes in the lipid and protein organization in a process known as capacitation, prepares the sperm to bind to the extracellular matrix that surrounds the egg (zona pellucida). The motility pattern of sperm also changes from being linear, to rapid and asymmetrical, in what is refered to as sperm hyperactiation. For successful fertilization, the sperm cell also need to go through the acrosome reaction, in which the acrosome membrane fuses with the plasma membrane of the spem head. This allows the acrosomal enzymes to degrade the extacellular matrix of the egg an exposes components necessary for binding to the underlying cell membrane of the egg. Membrane fusion then allows the sperm nucleus and the centrioles, but not the mitochondria to enter the egg, leading to the formation of a diploid zygote and initiation of embryonic development.

Infertility is a widespread condition that affect millions of couples around the globe (Cannarella R et al. (2020)). In half of the cases, male infertility causes or contributes to the inablility to achieve conception. This may result from defects during spermatogenesis, defects in sperm functionality in terms of reaching and fusing with the egg, or from factors that affect embryonal growth and development. While it was originally thought that the male contribution to fertilization was resticted to delivery of sperm DNA, recent years of studies have shown that proteins as well as RNA originating from the sperm cell are important for various aspects of fertilization and embryogenesis. In as much as 70% of the cases, the molecular targets of male infertility remains elusive, pointing towards a need for further studies of mechanisms and pathways underpinning sperm structure and function, including the detailed spatial architecture of proteins that can be found in sperm.

Gene Ontology (GO)-based functional enrichment analysis of genes encoding sperm proteins shows an enrichment of terms that are well in line with the known functions of the sperm cell. The most highly enriched terms for the GO domain Biological Process are related to sperm motility, assembly and organization of the cilium, and processes related to development (Figure 5a). Enrichment analysis of the GO domain Molecular Function reveal enrichment of terms describing binding to microtubules and motor proteins, as well as motor activity (Figure 5b).

Figure 5a. Gene Ontology-based enrichment analysis for the sperm proteome showing the significantly enriched terms for the GO domain Biological Process. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Figure 5b. Gene Ontology-based enrichment analysis for the sperm proteome showing the significantly enriched terms for the GO domain Molecular Function. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Sperm proteins with multiple locations

In the subcellular resource, approximately 76% (n=493) of the proteins that localize to the sperm cell and its substructures also localize to other cell compartments in other cell types (Figure 6). The network plot shows that the most common locations shared with the sperm cell are the mitochondria, cytosol, and nucleoplasm. Dual localizations with the mitochondria are overrepresented, while dual localizations with the plasma membrane are underrepresented.

Figure 6. Interactive network plot of sperm cell proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the sperm cell and its substructures, and to one or more additional locations in other cell types. Only connecting nodes containing at least 1.0% of the proteins in the sperm proteome are shown. The circle sizes are related to the number of proteins. The cyan colored nodes show combinations that are significantly overrepresented, while magenta colored nodes show combinations that are significantly underrepresented as compared to the probability of observing that combination based on the frequency of each annotation and a hypergeometric test (p≤0.05). Note that this calculation is only done for proteins with dual localizations. Each node is clickable and results in a list of all proteins that are found in the connected organelles.

Expression levels of sperm proteins in tissue

Transcriptome analysis and classification of genes into tissue distribution categories (Figure 7) shows that the genes encoding proteins localizing to the sperm cell and its substructures are more likely to be detected in a single or some tissues, but less likely to be ubiquitously expressed compared to all genes presented within the subcellular resource. Thus, these genes show a more restricted pattern of tissue expression compared to other genes, likely reflecting the specific function of the sperm cell and the many sperm-specific proteins.

Figure 7. Bar plot showing the percentage of genes in different tissue distribution categories for sperm protein-coding genes compared to all genes in the subcellular section. Asterisk marks a statistically significant deviation (p≤0.05) in the number of genes in a category based on a binomial statistical test. Each bar is clickable and gives a search result of proteins that belong to the selected category.

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