The fallopian tube-specific proteome

The fallopian tube transcriptome

Transcriptome analysis of the fallopian tube can be visualized with regard to specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the fallopian tube compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

• Tissue enriched: At least four-fold higher mRNA level in fallopian tube compared to any other tissues.
• Group enriched: At least four-fold higher average mRNA level in a group of 2-5 tissues compared to any other tissue.
• Tissue enhanced: At least four-fold higher mRNA level in fallopian tube compared to the average level in all other tissues.

Distribution, on the other hand, visualizes how many genes that have, or do not have, detectable levels (NX≥1) of transcribed mRNA molecules in the fallopian tube compared to other tissues. As evident in Table 1, all genes elevated in fallopian tube are categorized as:

• Detected in single: Detected in a single tissue
• Detected in some: Detected in more than one but less than one third of tissues
• Detected in many: Detected in at least a third but not all tissues
• Detected in all: Detected in all tissues

Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in fallopian tube as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (NX≥1) in fallopian tube as well as in all other tissues.

As shown in Figure 1, 312 genes show some level of elevated expression in the fallopian tube compared to other tissues. The three categories of genes with elevated expression in fallopian tube compared to other organs are shown in Table 1. In Table 2, the 6 enriched genes are defined.

Table 1. Number of genes in the subdivided categories of elevated expression in fallopian tube.

Table 2. The 6 genes with enriched expression in fallopian tube. "Tissue distribution" describes the transcript detection (NX≥1) in fallopian tube as well as in all other tissues. "mRNA (tissue)" shows the transcript level in fallopian tube as NX values. "Tissue specificity score (TS)" corresponds to the fold-change between the expression level in fallopian tube and the tissue with second highest expression level.

Protein expression of genes elevated in the fallopian tube

In-depth analysis of elevated genes in the fallopian tubes using antibody-based protein profiling allowed us to create a map of where these genes are expressed within the organ. An essential function of the fallopian tube is the mucociliary (mucus and cilia-assisted) transportation of gametes. As a natural consequence, most genes elevated in the fallopian tube are genes coding for cilium proteins, as well as some genes coding for tubular-secreted protein components.

Proteins expressed in ciliated cells

Cilia are small hair-like cell membrane coated microtubule structures projecting out from the surface of virtually all vertebrate cells, either as a single non-motile sensory monocilia, as motile multicilia on specialized ciliated cells or as the sperm tail flagellum. Motile multicilia of ciliated cells, like the ones lining the inside of the fallopian tube, facilitate the transportation of fluid. Except for microtubule proteins, cilia consist of many additional types of proteins important for cilium structure integrity and movement, and the role of many candidate genes are still left to be investigated. SNTN is suggested to be found at the tip of the cilium, acting as a structural protein, linking the cell-membrane to the underlying microtubule fibers. CFAP52 and CFAP53, recently discovered cilium-associated proteins with unknown function, also exhibit apparent protein expression at the top portion of the fallopian tube cilia.

SNTN
CFAP52
CFAP53

The forkhead transcription factor FOXJ1 activates transcription of genes that mediate the assembly of motile cilia. The proteins calcyphosin (CAPS) and calcyphosin-like (CAPSL) are uncharacterized calcium-binding proteins. Other poorly characterized proteins expressed in cilia are LRRC23 and C20orf85.

FOXJ1
SPAG6
CAPS
CAPSL
LRRC23
C20orf85

Proteins expressed in secretory cells

In addition to ciliated cells, the mucosal epithelial lining is also consist of secretory type cells, important for producing and secreting proteins and nutrients necessary for the regulation and survival of migrating gametes and the developing blastocyst. The oviductal glycoprotein 1 ( OVGP1) is secreted into the lumen and is shown to play an important role in pre-fertilization events.

OVGP1

Gene expression shared between the fallopian tube and other tissues

There are 75 group enriched genes expressed in fallopian tube. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including fallopian tube, compared to all other tissues.

In order to illustrate the relation of fallopian tube tissue to other tissue types, a network plot was generated, displaying the number of genes with shared expression between different tissue types.

Figure 2. An interactive network plot of the fallopian tube enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of fallopian tube enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 4 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

The fallopian tube shares expression of many elevated genes with the testis, several with the brain and a few with the epididymis, pituitary gland, lung and ovary. The common denominator is the utilization of cilia, or the structurally similar flagellum, for essential organ functions. DNAI2, a dynein protein, constitutes a motor protein component of motile cilia of multiciliated cells as well as the flagellum (tail) of the sperm, pulling on the microtubule structure of the cilium/flagellum to create motion and in the case of the sperm, sperm motility. DNAI2 protein can be observed mainly in cilia within the fallopian tube, as well as the flagellum of spermatids and cytoplasm of differentiating spermatocytes.

DNAI2 - fallopian tube
DNAI2 - testis

CACNA1B is a subunit of a N-type voltage-dependent calcium channel. CACNA1B is group-enriched in the fallopian tube, brain, adrenal gland, pituitary gland and testis.

CACNA1B - fallopian tube

CACNA1B - caudate
CACNA1B - adrenal gland
CACNA1B - testis

KLHL32 is an uncharacterized protein group-enriched in the fallopian tube and brain. MUC16 is a large mucus glycoprotein with the important function of creating a gel-like layer enabling mucociliary transport of the gametes and the fertilized ovum. MUC16 is group-enriched in the fallopian tube, salivary gland, cervix and adipose tissue.

KLHL32 - fallopian tube
KLHL32 - caudate

MUC16 - fallopian tube
MUC16 - cervix, uterine
MUC16 - salivary gland

Fallopian tube function

The physiological role of fallopian tubes is to facilitate the transport of female and male gametes towards each other, act as a site for fertilization and to facilitate the subsequent transport of the fertilized ovum to the site of implantation in the uterine endometrium.

Fallopian tube transportation is not completely understood but is currently thought to be regulated through a combination of mechanisms involving different tubular tissue types. The tubular structure consists of an outer serosa coat, underlying layers of smooth muscle (the myosalpinx), and an inner luminal mucosa consisting of a surface epithelial lining and an underlying stromal layer.

Transport within the fallopian tube is bidirectional. The ovum is transported towards the uterus, while the sperm moves towards the ovaries. Transportation of the ovum through the lumen of the fallopian tube is believed to be facilitated through a combination of muscular (peristaltic) contractions of the myosalpinx and the swaying movement of hair-like structures found on the luminal surface of ciliated cells of the epithelial lining, called cilia, which creates a flow towards the uterus. Sperm, on the other hand, is able to go in the opposite direction, towards the ovary, to meet up with the ovum in the ampulla segment of the fallopian tube. The opposite motion of sperm is currently believed to be regulated by peristaltic contractions of the myosalpinx and hyperactive flagellar swimming motion of the sperm through the secretions produced by the secretory cells of the epithelial lining.

The structure of the tubular mucosa varies along the length of the fallopian tube in accordance with its regional function. In the infundibulum and ampulla, wide tubular parts of the fallopian tube close to the ovarian end, the mucosa is highly folded, creating an optimal environment for ovum capture and subsequent fertilization. In contrast, in the narrow tubular parts closest to the uterus, the mucosa is significantly less folded, facilitating the rapid transportation of sperm and the fertilized ovum.

Figure 3. The ovaries, fallopian tubes and uterus. The menstrual cycle can be described both by the ovarian cycle and the uterine cycle which consists of menstruation, proliferative phase, and secretory phase. During the proliferative phase the lining of the uterus grow, or proliferate, and follicles in the ovary start to mature. During ovulation, the dominant follicle releases an ovum (egg), which moves into the fallopian tube. Inside the fallopian tube, the released ovum potentially meets up and fuses with a sperm (fertilization), develops into a blastocyst and moves into the uterus where it is implanted into the endometrium. In the ovary, after ovulation and during the secretory phase, the remaining parts of the follicle that released the egg transforms into the corpus luteum which produces hormones that support the early stage of pregnancy. If the ovum is not fertilized, the follicle will atrophy, leading to falling levels of hormones and the beginning of menstruation and a new cycle.

Fallopian tube histology

The normal fallopian tube extends from the area of its corresponding ovary to its terminus in the uterus. The tube measures between 9-11 cm in length. At the ovarian end, the tube opens into the peritoneal cavity and is composed of approximately 25 finger-like projections termed the fimbriae. In its extrauterine course, the fallopian tube is enveloped in a peritoneal fold along the superior margin of the broad ligament.

The fallopian tube is histologically composed of three layers: a mucosal membrane, a wall of smooth muscle and a serosal coat. The serosa is lined by flattened mesothelial cells. The muscularis mucosae is composed of two layers: an outer longitudinal and an inner circular layer. There is additionally, an inner longitudinal layer in the intramural segment of the tube that extends for 2 cm laterally. The inner circular layer forms the bulk of the muscular coat. The outer longitudinal layer comprises inconspicuous smooth muscle cells interspersed with loose connective tissue.

The mucosa rests directly on the muscularis. It consists of a luminal epithelial lining and a scant underlying lamina propria with sparse spindle and angulated cells. The luminal complexity is more marked towards the ovarian end compared to the interstitial and isthmic portions containing only five to six blunt papillae.

Three histologic cell types comprise the epithelial layer: ciliated (20-30%), secretory (55-60%) and intercalary cells. Ciliated cells are believed to be more frequent in the ovarian end of the fallopian tube. The ciliated cell has a columnar shape and contains an oval or round nucleus, often located perpendicular or parallel to the long axis of the cell. The secretory cell is usually a more narrow columnar cell with approximately the same height as the ciliated cell. The nucleus is ovoid and perpendicular to the long axis of the cell. The chromatin is denser and the nucleolus smaller than that seen in the ciliated cell. The intercalary cell, or peg cell is a columnar cell occupied chiefly by a thin, dark-staining nucleus.

The histology of human fallopian tube including detailed images and information can be viewed in the Protein Atlas Histology Dictionary.

Background

Here, the protein-coding genes expressed in fallopian tube are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in fallopian tube.

Transcript profiling was based on a combination of three transcriptomics datasets (HPA, GTEx and FANTOM5), corresponding to a total of 9332 samples from 113 different human normal tissue types. The final consensus normalized expression (NX) value for each tissue type was used for classification of all genes according to the tissue specific expression into two different categories, based on specificity or distribution.

Relevant links and publications

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu NY et al., Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res. (2015)
PubMed: 26117540 DOI: 10.1093/nar/gkv608

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

Histology dictionary - fallopian tube