DAZ protein family

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The DAZ (Deleted in AZoospermia) protein family is a group of three highly conserved RNA-binding proteins that are important in gametogenesis and meiosis. Therefore, mutations in the genes that encode for the DAZ proteins can have detrimental consequences for fertility. [1]

Contents

The three members of the DAZ protein family include BOULE (BOLL), DAZL (DAZLA) and DAZ (DAZ1, DAZ2, DAZ3 and DAZ4). DAZ1 is located on the Y chromosome in higher primates and is important for spermatogenesis. BOULE and DAZL are important for both oogenesis and spermatogenesis. BOULE and DAZL are both located on autosomes as single copies. However DAZ is located with multiple copies in the Y chromosome only. BOULE is present from invertebrates, DAZL is from vertebrates and DAZ is present from primates. [2]

Discovery

Each DAZ protein family member was discovered individually, over a period of time by different research groups. BOULE was first identified in Drosophila, with homologs being found in other organisms, from sea anemone to humans , DAZL is thought to have come from BOULE by a gene duplication event and was first discovered in mice, but is present in all vertebrates, and the Y-chromosomal DAZ gene was first found in infertile males, but is also present in apes and Old World monkeys. [2] DAZ arose during primate evolution by (i) transposition (moving) from the autosomal gene to the Y chromosome, (ii) removing unwanted parts of Exons within the transposed gene and (iii) amplification (making multiple copies) of the modified gene. [3]

Mechanism of action

The DAZ family of proteins have multiple mechanisms of action with varying regulatory effects on translation. [1] The proteins exert their action on target mRNAs by binding various 3’-UTR sequences via their conserved RNA recognition motif. DAZL, which binds the GUU sequence of target mRNAs, interacts with poly(A)-binding proteins (PABPs) to initiate translation. PABPs consequently bind to the poly(A) tails of target mRNAs and cause the 5’ end to fold over, bringing it into close proximity with the 3’ end. This aids the recruitment of ribosomal units and hence the initiation of translation. [4] This is an important function of DAZL as many mRNAs within germ cells have short pol(A)-tails and would therefore not be recruited for translation without the assistance of DAZL. [1]

DAZ and DAZL also interact with the translationally repressive RNA Binding Protein PUM2 from the Pumilio RBP family. [5] PUM2 interacts with both the conserved RRM and DAZ regions to form a complex which can interact other mRNAs to regulate their translation. Although the mechanism of this complex is not fully understood, it is thought that due to the inhibitory role of independent PUM2, the combination of both DAZ/DAZL and PUM2 will exert similar repressive effects. [1]

Family characteristics

DAZ family of proteins are mRNA translation regulators with a characteristic recognition motif for binding target mRNAs and a sequence of 24 amino acids that is characteristic to the family, named DAZ repeats. [2] The characteristic structure of the protein family is a single RRM-like RNA-binding domain at the N-terminus (amino terminus) and amino acid repeats in the C-terminus (carboxy terminus). DAZ protein family is one of the few examples of a tissue-specific RNA-binding protein that acts as a developmental regulator. [6] In mice and humans, DAZ protein is non-uniformly distributed in the cytoplasm of pre-meiotic germ cells due to its oligomerisation with itself. However, there are currently not relevant data for DAZL and BOULE. None of the family members is found in plants or fungi suggesting the DAZ family is an animal specific family of reproduction genes.

Conservation among species

Expression of DAZ proteins varies between species but is mainly expressed in Primordial Germ Cells (PGCs). One DAZ homologue is expressed in nearly every stage of spermatogenesis, from PGCs to mature spermatozoa. [5] The conservation of DAZ family genes among various species ranging from unicellular organisms to humans indicates their important role in fertility. [5] More precisely, DAZ is only present in higher primates, without any homologues being present in unicellular organisms whereas BOULE is found in species ranging from sea anemones to humans and DAZL is conserved among vertebrates. [2] BOULE was the first gene originating, while DAZ evolved from DAZL during primate evolution resulting in a 90% similarity in humans. [2]

Clinical significance

In humans, 50% of infertility issues are caused by males, [2] and of this, genetic deletions in the Y chromosome make up a lot of this majority, since only men have the Y chromosome. DAZ gene in present on Y chromosome and deletion of this gene has been directly shown as a main cause of infertility. This causes no sperm cell found in semen and it is termed Azoospermia. One DAZ homologue is expressed in nearly every stage of spermatogenesis, from Primordial Germ Cells (PGCs) to mature spermatozoa. [5]

DAZ is not absolutely required for spermatogenesis as some DAZ deleted men are still able to father children. DAZ pushes ESCs in to germ cells with molecular features of being spermatids. [5]

DAZL is expressed in humans from early progenitor germ cell migration, right up to spermatozoa differentiation. Since DAZL is located on an autosome, it has been shown to be important in germ cell development of both oocyte and spermatocytes (in spermatogenesis and oogenesis), albeit in different expression patterns for both.

Related Research Articles

Germ cell

A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

Spermatogenesis

Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubules. These cells are called spermatogonial stem cells. The mitotic division of these produces two types of cells. Type A cells replenish the stem cells, and type B cells differentiate into primary spermatocytes. The primary spermatocyte divides meiotically into two secondary spermatocytes; each secondary spermatocyte divides into two equal haploid spermatids by Meiosis II. The spermatids are transformed into spermatozoa (sperm) by the process of spermiogenesis. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa and four haploid cells.

Male infertility refers to a male's inability to cause pregnancy in a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.

Azoospermia factor (AZF) refers to one of several proteins or their genes, which are coded from the AZF region on the human male Y chromosome. Deletions in this region are associated with inability to produce sperm. Subregions within the AZF region are AZFa, AZFb and AZFc. AZF microdeletions are one of the major causes of male infertility for azoospermia and severe oligozoospermia males. AZF is the term used by the HUGO Gene Nomenclature Committee.

Piwi

Piwi genes were identified as regulatory proteins responsible for stem cell and germ cell differentiation. Piwi is an abbreviation of P-elementInduced WImpy testis in Drosophila. Piwi proteins are highly conserved RNA-binding proteins and are present in both plants and animals. Piwi proteins belong to the Argonaute/Piwi family and have been classified as nuclear proteins. Studies on Drosophila have also indicated that Piwi proteins have slicer activity conferred by the presence of the Piwi domain. In addition, Piwi associates with heterochromatin protein 1, an epigenetic modifier, and piRNA-complementary sequences. These are indications of the role Piwi plays in epigenetic regulation. Piwi proteins are also thought to control the biogenesis of piRNA as many Piwi-like proteins contain slicer activity which would allow Piwi proteins to process precursor piRNA into mature piRNA.

CPEB, or cytoplasmic polyadenylation element binding protein, is a highly conserved RNA-binding protein that promotes the elongation of the polyadenine tail of messenger RNA. CPEB most commonly activates the target RNA for translation, but can also act as a repressor, dependent on its phosphorylation state. In animals, CPEB is expressed in several alternative splicing isoforms that are specific to particular tissues and functions, including the self-cleaving Mammalian CPEB3 ribozyme. CPEB was first identified in Xenopus oocytes and associated with meiosis; a role has also been identified in the spermatogenesis of Caenorhabditis elegans.

PABPC1

Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene. The protein PABP1 binds mRNA and facilitates a variety of functions such as transport out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA.

DAZL

Deleted in azoospermia-like is a protein that in humans is encoded by the DAZL gene.

DAZ1

Deleted in azoospermia 1, also known as DAZ1, is a protein which in humans is encoded by the DAZ1 gene.

USP9Y

Ubiquitin specific peptidase 9, Y-linked , also known as USP9Y, is an enzyme which in humans is encoded by the USP9Y gene. It is required for sperm production. This enzyme is a member of the peptidase C19 family and is similar to ubiquitin-specific proteases, which cleave the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins.

Deleted in azoospermia protein 3 is a protein that in humans is encoded by the DAZ3 gene.

DAZ2

Deleted in azoospermia protein 2 is a protein that in humans is encoded by the DAZ2 gene.

DAZ associated protein 1

DAZ-associated protein 1 is a protein that in humans is encoded by the DAZAP1 gene.

PUM2

Pumilio homolog 2 is an RNA-binding protein that in humans is encoded by the PUM2 gene.

RNA binding motif protein, Y-linked, family 1, member A1

RNA-binding motif protein, Y chromosome, family 1 member A1/C is a protein that in humans is encoded by the RBMY1A1 gene.

DDX3Y

ATP-dependent RNA helicase DDX3Y is an enzyme that in humans is encoded by the DDX3Y gene.

BOLL

Protein boule-like is a protein that in humans is encoded by the BOLL gene.

Sperm-associated antigen 8

Sperm-associated antigen 8 is a protein that in humans is encoded by the SPAG8 gene.

DAZAP2

DAZ-associated protein 2 is a protein that in humans is encoded by the DAZAP2 gene.

Vasa is an RNA binding protein with an ATP-dependent RNA helicase that is a member of the DEAD box family of proteins. The vasa gene, is essential for germ cell development and was first identified in Drosophila melanogaster, but has since been found to be conserved in a variety of vertebrates and invertebrates including humans. The Vasa protein is found primarily in germ cells in embryos and adults, where it is involved in germ cell determination and function, as well as in multipotent stem cells, where its exact function is unknown.

References

  1. 1 2 3 4 Fu XF, Cheng SF, Wang LQ, Yin S, De Felici M, Shen W (2015). "DAZ Family Proteins, Key Players for Germ Cell Development". International Journal of Biological Sciences. 11 (10): 1226–35. doi:10.7150/ijbs.11536. PMC   4551758 . PMID   26327816.
  2. 1 2 3 4 5 6 Reynolds N, Cooke HJ (January 2005). "Role of the DAZ genes in male fertility". Reproductive Biomedicine Online. 10 (1): 72–80. doi: 10.1016/s1472-6483(10)60806-1 . PMID   15705297.
  3. ↑ Dhanoa JK, Mukhopadhyay CS, Arora JS (July 2016). "Y-chromosomal genes affecting male fertility: A review". Veterinary World. 9 (7): 783–91. doi:10.14202/vetworld.2016.783-791. PMC   4983133 . PMID   27536043.
  4. ↑ Goss DJ, Kleiman FE (March 2013). "Poly(A) binding proteins: are they all created equal?". Wiley Interdisciplinary Reviews: RNA. 4 (2): 167–79. doi:10.1002/wrna.1151. PMC   3580857 . PMID   23424172.
  5. 1 2 3 4 5 Vangompel MJ, Xu EY (January 2011). "The roles of the DAZ family in spermatogenesis: More than just translation?". Spermatogenesis. 1 (1): 36–46. doi:10.4161/spmg.1.1.14659. PMC   3329454 . PMID   22523742.
  6. ↑ Yen PH (June 2004). "Putative biological functions of the DAZ family". International Journal of Andrology. 27 (3): 125–9. doi: 10.1111/j.1365-2605.2004.00469.x . PMID   15139965.
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