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Human genetics and disease

Mouse models of male infertility

Key Points

  • Male infertility accounts for 5–7% of infertility in human couples. Treatment so far is limited and, in most cases, the couples have to resort to IVF techniques that circumvent rather than treat this problem.

  • Many environmental, behavioural and genetic factors affect male fertility, with the genetic contribution estimated at 60%.

  • Spermatogenesis is a complex process that involves stem-cell renewal, genome reorganization and genome repackaging that culminates in the production of motile gametes.

  • Because of the complex interaction between the soma and the germline during spermatogenesis, the process cannot be recapitulated in vitro.

  • Although there are differences between spermatogenesis in mouse and man, the similarities are sufficient to use the mouse as a model of human spermatogenesis.

  • Mouse mutants have been invaluable in obtaining information on all aspects of spermatogenesis, at both fetal and post-natal stages.

  • Although we have a long way to go before we can treat male infertility, techniques developed in the mouse, such as germ-cell transplantation have already found their way to the clinic.

Abstract

Spermatogenesis is a complex process that involves stem-cell renewal, genome reorganization and genome repackaging, and that culminates in the production of motile gametes. Problems at all stages of spermatogenesis contribute to human infertility, but few of them can be modelled in vitro or in cell culture. Targeted mutagenesis in the mouse provides a powerful method to analyse these steps and has provided new insights into the origins of male infertility.

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Figure 1: Stages of spermatogenesis.
Figure 2: Organization of the testis.
Figure 3: Hormonal regulation of spermatogenesis.

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DATABASES

LocusLink

activin

activin receptor

AR

Ar

Atm

ATM

Atr

AZFa

AZFc

Bol

Brca1

Brca2

CFTR

Crem

CREM

Cul3

Cyp19

cyritestin

Dazl

Dazl1

Dby10

Dmc1h

Dmrt1

DMRT1

Eif2s3y

Erg4

ESR1

ESR2

Facl3

Fanconi anaemia group C

Farsl

fertilin-β

FSH

Fshr

Gdnf

H2afx

inhibin

jsd

Kcne4

Kit

LH

LHR

Mm

Nr5a1

Prm1

Prm2

Rad51

Scg2

Serpine2

Smcy

Spo11

Sry

Sycp3

Theg

Tlf/Trf2

Tnp1

Tnp2

Ube2a

Ube2b

UBE2B

Ubely1

Usp9y

Uty

OMIM

ataxia telangiectasia

cystic fibrosis

Fanconi anaemia

Sertoli-cell-only syndrome

<i>Saccharomyces</i> Genome Database

RAD6

Glossary

RNAi

A phenomenon in which the expression of a gene is temporarily inhibited when a double-stranded complementary RNA is introduced into the organism.

SPERMATOGONIUM

A diploid male germ cell that divides mitotically to produce stem cells or cells that enter meiosis.

PITUITARY GLAND

An endocrine gland that is located at the base of the brain, and that produces hormones, such as growth hormone, luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone.

SEMINIFEROUS TUBULE

A structural unit in the adult testis; it consists of somatic Sertoli cells and germ cells at several developmental stages.

SPERMIOGENESIS

The stage of spermatogenesis during which spermatids undergo cell remodelling and DNA compaction.

SPERMIATION

The release of mature spermatozoa from the surface of the Sertoli cell into the lumen of the seminiferous tubule.

SPERMATOCYTE

A cell that is progressing through meiotic prophase.

SPERMATID

A post-meiotic, haploid germ cell.

ADRENAL GLAND

A gland located on top of the kidney that produces hormones that regulate aspects of physiology, such as the heart rate and blood pressure.

SYNAPTONEMAL COMPLEX

A structure that holds paired chromosomes together during prophase 1 of meiosis and that promotes genetic recombination.

CHECKPOINT

Quality-control points during the cell cycle that ensure that each phase of the cycle is completed successfully before the process is allowed to continue.

PROTAMINE

Small arginine-rich proteins that are deposited on DNA towards the end of sperminogenesis.

ACROSOME

This structure arises from the Golgi complex. It first develops in spermatids and eventually forms a cap structure over the nucleus in the mature spermatozoa.

TRANSITION PROTEINS

Small basic nuclear proteins that replace histones on germ cell DNA. When DNA compaction begins they, in turn, are replaced by protamines.

HAPLOINSUFFICIENCY

A phenotype that arises in diploid organisms owing to the loss of one functional copy of a gene.

GONOCYTES

Once the gonad has differentiated into a testis by forming seminiferous cords, primitive germ cells are referred to as gonocytes.

GENE TRAP

A DNA construct that contains a reporter gene sequence downstream of a splice acceptor site that is capable of integrating into random chromosomal locations in mouse. Integration of the gene trap into an intron allows the expression of a new mRNA containing one or more upstream exons followed by the reporter gene.

KNOCKING DOWN

Removing function of a gene in a transient way, such as by RNAi.

AUTOLOGOUS GERM-CELL TRANSPLANTATION

Transplantation of spermatogonial stem cells (As) from one animal into that of a recipient in which germ cells are missing.

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Cooke, H., Saunders, P. Mouse models of male infertility. Nat Rev Genet 3, 790–801 (2002). https://doi.org/10.1038/nrg911

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