The knockout mice models for mouse Ly6 genes with human orthologs—namely Ly6E, Ly6K, Lynx1, Slurp1, and Gpihbp1 have been described (Table 1). The other family members have not been characterized in the knockout mice model. The phenotype and the characterization of the known knockout mice models are as described below, which offer important insight into the function of these genes.

Ly6E: The mouse Ly6E gene was deleted by gene targeting in mice to create homozygous knockout mice (8). Animals with a Ly6E^−/− mutation showed embryonic lethality at E14.5. It was though that embryonic lethality was due to cardiac malformation. It was later resolved that Ly6E knockout induced lethality was due the critical role of Ly6E in the trophoblast stem cells (9). The trophoblast forms the outer layer of fetal part of the placenta. Ly6E is expressed specifically in the syncytiotrophoblast (SynT-I) cells (10). Ly6E was found to be a possible receptor for Syncytin A ligand (11). The syncytiotrophoblast layer of fetal placenta play important role in connecting with maternal placenta for the proper exchange of nutrients. In the absence of Ly6E in the fetal placenta, this fetal-maternal placental vascularization is not well-formed causing harm to the fetus. The role of Ly6E in human placental development has not yet been described. Thymic development was found to be normal in Ly6E^−/− mice, suggesting that Ly6E may play a redundant role in thymic development and development of immune cells.

Ly6K: The mouse Ly6K gene knockout mice were generated using a targeting vector substituting exons 2, 3, and 4 (12). Adult Ly6K^−/− mutant male mice were found to be infertile. Female Ly6K^−/− mutant mice had normal fertility. Ly6K is not expressed in mature spermatozoa, however the spermatozoa from Ly6K^−/− mutant male mice were unable to migrate into the oviduct (12). The reason for Ly6K associated migration defects in sperm of adult mice is not yet known. The role of Ly6K in human sperm related infertility is not yet described.

Slurp1: The mouse Slurp1 gene is a secreted member of the Ly6 gene family. The deficiency and mutations in human SLURP1 gene causes Mal de Meleda (MDM), a rare autosomal recessive genetic disease, characterized by inflammatory palmoplantar keratoderma (13, 14). Slurp1^−/− mutant mice exhibit this rare palmoplantar keratoderma, and show metabolic phenotypes such as reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and neuromuscular abnormalities such as hind-limb clasping (15).

Gpihbp1: Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (Gpihbp1) deficient mice on a regular chow diet display accumulation of chylomicrons in the plasma and high plasma triglyceride levels (16). Gpihbp1^−/− mice show reciprocal metabolic perturbations in adipose tissue and liver due to defective lipolysis (17). These results suggest that human GPIHBP1 gene may play important role in the lipolytic processing of triglyceride-rich lipoproteins.

Lynx1: Ly6 neurotoxin1 (Lynx1) knockout mice display increased visual cortex plasticity in mice (18). The Lynx1^−/− phenotype was partially derived from the inhibition of nicotinic acetylcholine receptor signaling by Lynx1 (18). These results suggest that human LYNX1 gene may play important role in nicotine response in the brain.

The expression of many mouse Ly6 gene family proteins are lineage specific and their expression coincides with the differentiation stages of leukocyte cell populations as seen in the mouse model. The role of human LY6 genes in immune cells differentiation is still not clear. These properties have made them attractive targets to be used for subset identification of leukocytes in vitro and antibody-mediated depletion of specific immune cell populations in vivo. Recently, Nigrovic et al. summarized the mRNA expression of mice Ly6 genes in B-cells, T-cells, NK cells, monocytes, and dendritic cells based on data from the Immgen database (3). Ly6E RNA expression was expressed on all tested immune cell subtypes in the Immgen database. Ly6D RNA was expressed in B-cells, T-cells and dendritic cells. Lypd2, which was described in non-classical monocytes (19). Ly6F, Ly6H, Ly6K, Gml, Psca, Gpihbp1 RNA expression was not found to be associated with expression on immune cells in mice. Interestingly, the mice genes namely Sca1, Ly6B, Ly6C, Ly6G, Ly6I/Ly6M, and Ly6F RNA expression have found to be expressed on many immune cells types in mice. These genes do not have human orthologs. It is yet to be discovered which human genes may function similar to these mice genes. The mRNA expression for Ly6A/Sca1 was found to be present in B-cells, T-cells and dendritic cells (3). Ly6B RNA expression was found in NK cells, monocytes and neutrophils but absent from B-cells, T-cells and dendritic cells. Ly6C RNA expression was found to be present in all subsets except T cells. Ly6G RNA expression was only present in neutrophils and absent from all other cell types analyzed. Ly6I/Ly6M RNA expression was present only in monocytes and neutrophils and absent in all other cell types. It has been shown that RNA and protein expression for some of the human LY6 gene family members such as GML (20, 21), LY6K (22, 23), PSCA (24, 25), and LY6E (23, 26) have immune-modulatory properties in tumor microenvironment.

LY6E and LY6D are the only two genes on human chromosome 8 with a mouse ortholog on chromosome 15, for which some data is available to describe their expression and function in immune cells using mouse models, as discussed below. These genes have been shown to be important in the proliferation and differentiation of immune cells using mainly in vitro methods (3, 27). The mechanistic basis behind the differentiation specific expression remains to be fully understood.

Ly6D: The mRNA for mouse Ly6D gene was found to be present in B-cells, T-cells and dendritic cells and absent in NK cells, monocytes, and neutrophils (3). Recent in vitro studies indicate that Ly6D gene is expressed in common lymphoid progenitors which arise from hematopoietic stem cells and give rise to B-lineage lymphocytes (28). Mouse Ly6D gene expression is associated with B-cell specification (29). Ly6D and SiglecH gene expression positive cells from IL7R positive lymphoid progenitor cell populations were committed to become plasmacytoid dendritic cells, while double negative cells were uncommitted. Plasmacytoid dendritic cells are an immune subset devoted to the production of high amounts of type 1 interferon in response to viral infections (30).

Ly6E: The mouse Ly6E gene is expressed in peripheral B-cells, immature T-cells, activated T cells, thymus stromal cells, and macrophages (3). A functional role of Ly6E was reported in maintenance of self-renewal of erythroid progenitors (31).

LY6D: Human LY6D RNA and protein is expressed in normal esophageal and skin as published by the human protein atlas on www.proteinatlas.org (32–36).

LY6E: Human LY6E RNA is expressed in normal liver, fetal placenta, lung, and spleen (32–36).

LY6H: Human LY6H RNA is expressed in brain (32–36).

LY6K: Human LY6K RNA and protein is expressed in normal testis (32–36).

PSCA: Human PSCA RNA is expressed in prostate, urinary bladder, and esophagus (32–36).

LYPD2: Human LYPD2 RNA is expressed in esophagus and tonsil (32–36).

SLURP1: Human SLURP1 RNA is expressed in esophagus and skin (32–36).

GML: Human GML RNA is expressed in testis and adrenal gland (32–36).

GPIHBP1: Human GPIHBP1 RNA is expressed in adipose, lung, breast, brain, heart and soft (32–36).

The LY6D, LY6E, Ly6K, and Ly6H RNA is expressed at high levels compared to adjacent normal tissues in a multitude of tumors including ovarian, colorectal, gastric, breast, lung, bladder, brain and CNS, cervical, esophageal, head and neck, and pancreatic cancer. The increased expression of LY6D, LY6E, LY6K, and LY6H was associated with poor survival in ovarian, colorectal, gastric, breast, and lung cancer (37) (Table 2). The casual reason for the increased expression of LY6 family proteins and the poor survival outcome is not yet established. As discussed further in the review under cell signaling heading, LY6 proteins play important role in TGFβ signaling, AKT pathways and immune regulation. A cumulative effect of Ly6 downstream pathways may lead to increased aggressiveness of cancer cells and leading to poor survival outcome. More mechanistic studies will need to be performed to determine the precise pathways responsible for poor survival outcome in patients.

LY6D: Recent clinical outcome data added and published by Km plotter web tool show that increased RNA expression of LY6D is associated with poor prognosis in renal clear cell carcinoma and pancreatic ductal adenocarcinoma [Figure 1, (38)]. Recently, LY6D expression—in addition to OLFM4 and S100A7—was found to be associated with distant metastasis of estrogen receptor positive breast cancer (39). LY6D has also been shown to be increased in aggressive forms of head and neck cancer (40).

LY6E: Recent data also show that increased expression of LY6E is associated with poor overall survival of renal papillary cell carcinoma and is a good prognostic marker for renal clear cell carcinoma [Figures 2A,B, (38)]. These new data indicated that increased expression of LY6E is associated with poor overall survival of pancreatic ductal adenocarcinoma [Figure 2C, (38)]. The use of genome wide data analysis has prompted several new reports showing increased expression of Ly6E in bladder cancer, gastric cancer (39, 40). The LY6E gene has been also associated with more aggressive stem like cells in hepatocellular carcinoma, pancreatic carcinoma, colon, and kidney (41–43).

LY6H: Recent data shows that increased expression of Ly6H is associated with poor overall survival of renal clear cell carcinoma and pancreatic ductal adenocarcinoma [Figure 3, (38)].

LY6K: Increased expression of LY6K has also been reported in metastatic ER positive breast cancer (41–43), esophageal squamous cancer (44), gingivobuccal cancers (45), bladder cancer (46), and lung cancer (47). Recent data also show that increased expression of LY6K is associated with poor overall survival of renal clear cell carcinoma, renal papillary cell carcinoma and uterine corpus endometrial carcinoma [Figure 4, (38)].

PSCA: Prostate stem cell antigen (PSCA) RNA is expressed at high levels compared to adjacent normal tissues in prostate and pancreatic tumors as well as in glioma (48, 49). PSCA is downregulated in esophageal squamous cell carcinoma where it can act as a tumor suppressor by facilitating the nuclear translocation of RB1CC1 (50). Bioinformatics studies have indicated that polymorphisms rs2294008 in the PSCA gene may be prognostic in nature, however this association remains inconclusive due to contradictory observation and a lack of in vitro or in vivo experimental evidence (51–53).

LYPD2: LYPD2 RNA is expressed at high levels compared to adjacent normal tissues in cervical and head and neck cancer are associated with a favorable prognosis as shown by the human protein atlas (32).

SLURP1: SLURP1 RNA expression is reduced in metastatic melanoma (13). The prognostic value of Slurp1 is unknown.

GML: GML RNA expression is increased in non-small cell lung carcinoma (NSCLC) expressing wild-type P53 or P53 negative tumors. This specific expression of GML in P53 negative tumors was found to be linked to cisplatin sensitivity in NSCLC (54). The prognostic value of GML is not clear.

GPIHBP1: GPIHBP1 RNA and protein is increased in renal cancer (32–35). The prognostic value of GPIHBP1 is unknown.

LY6D: A single nucleotide polymorphism rs2572886 found in the human LY6D and Ly6PD2 genes is associated with cellular infection susceptibility to HIV-1 in lymphoblastoid B-cells and in primary T-cells and was also associated with accelerated disease progression in one of two cohorts of HIV-1–infected patients (55).

LY6E: LY6E expression is up-regulated during chronic HIV infection (26, 56). Using a HIV pathogenesis model, it was shown that LY6E can down-regulate monocyte responsiveness by modulating CD14 expression via an unknown mechanism (26). Recently, LY6E was shown to enhance viral infectivity IFN dependent fashion (57).

GPIHBP1: GPIHBP1 is an endothelial cell specific protein. It facilitates triglyceride (TG) lipolysis in the endothelial cells surface by binding to lipoprotein lipase (LPL), which releases nutrients to surrounding tissues (58). Four missense mutations in highly conserved residues in GPIHBP1 (C65Y, C65S, C68G, and Q115P) gene were identified in severe chylomicronemia leading to buildup of triglyceride causing health issues such as pancreatitis (59).

The LY6 proteins are glycosylphosphatidylinositol (GPI)-anchored cell surface proteins, the regulation of LY6 RNA and protein is not yet understood very well.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.