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  • Review Article
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The makings of maleness: towards an integrated view of male sexual development

Nature Reviews Genetics volume 7, pages 620–631 (2006)Cite this article

Key Points

  • The correct development of two distinct sexes from a sexually undifferentiated, bipotential embryo is a multi-step process that is essential for mammalian reproduction.

  • Disorders of sexual development in humans are surprisingly common, but most remain unexplained at the molecular level.

  • In mammals, male development is initiated by the expression of the male-determining Y-chromosomal gene Sry in the bipotential genital ridge, resulting in the differentiation of Sertoli cells. These in turn orchestrate the differentiation of all other cell types in the developing testes.

  • Hormones produced by the testes influence the development of other male sexual characteristics: anti-Müllerian hormone results in the degeneration of the female-specific Müllerian duct, insulin-like 3 hormone is responsible for testicular descent, and androgens control the male-specific differentiation of the genital tract, prostate, external genitalia and brain.

  • In addition to steroid hormones, a specific set of genes is required for each differentiation step. These sets of genes build a network of gene regulation and signal-transduction pathways, which involves a common series of 'hub' genes that are important for most, if not all, processes, in addition to tissue-specific genes.

  • Evidence exists that Sry and/or other genes are directly involved in sexual dimorphism of the brain.

  • Further work is required to unravel the broader spectrum of events that are involved in male development, moving beyond the issue of how testes differentiate.

  • Included in this is the challenge to resolve the mechanisms that drive the coordination and integration of the different systems (testes, genital tract, accessory organs, external genitalia and brain) that contribute to normal male anatomy and physiology.

Abstract

As the mammalian embryo develops, it must engage one of the two distinct programmes of gene activity, morphogenesis and organogenesis that characterize males and females. In males, sexual development hinges on testis determination and differentiation, but also involves many coordinated transcriptional, signalling and endocrine networks that underpin the masculinization of other organs and tissues, including the brain. Here we bring together current knowledge about these networks, identify gaps in the overall picture, and highlight the known defects that lead to disorders of male sexual development.

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Figure 1: Major steps in male sexual differentiation.
Figure 2: Histological and gene-expression map of an early embryonic testis.
Figure 3: Schematic representation of the differentiation of the male genital tract.
Figure 4: Development of the external genitalia.
Figure 5: Morphological and gene-expression changes during prostate development.
Figure 6: Overview of genetic pathways that drive male sexual differentiation in mammals.

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Acknowledgements

We thank T. Svingen, A. Combes and C. Spiller for helpful comments on the manuscript, and G. Yamada for help with Supplementary information S1. DW acknowledges grant funding by the US National Institutes of Health. PK is an Australian Professorial Research Fellow of the Australian Research Council and acknowledges grant funding by the Australian Research Council and the National Health and Medical Research Council, Australia.

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Authors and Affiliations

  1. Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia

    Dagmar Wilhelm

  2. ARC Centre of Excellence in Biotechnology and Development, Institute for Molecular Bioscience, The University of Queensland.,

    Peter Koopman

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  1. Dagmar Wilhelm
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Correspondence to Peter Koopman.

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DATABASES

OMIM

androgen insensitivity syndrome

ATRX syndrome

congenital bilateral aplasia of vas deferens

hand-foot-genital syndrome

Swyer syndrome

FURTHER INFORMATION

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Glossary

Hypospadias

Incorrect placement of the urethral opening in males, not at the tip of the penis.

Eutherian mammals

Mammals that have a placenta; includes all mammals except monotremes and marsupials.

Ovotestes

Gonads in which ovarian and testicular tissue are present together.

XY true hermaphroditism

This condition comprises the presence of both ovarian and testicular tissue either in the same gonad as an ovotestis, or an ovary and a testis.

XY gonadal dysgenesis

This can lead to pure gonadal dysgenesis, in which patients have streak gonads (undeveloped gonadal structures), Müllerian structures (owing to insufficient AMH secretion) and a complete absence of virilization. Alternatively, patients can have dysgenetic testes. In this case, enough AMH is produced to regress the Müllerian duct and there might be enough testosterone for partial virilization.

Campomelic dysplasia

A syndrome that is characterized by skeletal abnormalities and sex reversal, caused by mutations in SOX9.

Lissencephaly

A brain malformation that is characterized by the incomplete development of the folds of the outer region of the brain (the cerebral cortex), which causes the surface of the brain to appear abnormally thickened and unusually smooth.

Ovarian follicle

A cyst in which the oocyte matures.

Cryptorchidism

The condition of having undescended testes.

Persistent Müllerian duct syndrome

A rare form of male pseudohermaphroditism that is most commonly characterized by bilateral fallopian tubes and a uterus combined with an otherwise more or less normal male phenotype.

Anlage

A group of cells that are destined to become a specific structure or tissue in the adult, but have not yet differentiated.

Branchial arches

A series of paired segmental structures that are composed of ectoderm, mesoderm and neural crest cells that are positioned on each side of the developing pharynx. In mammals, the branchial arches contribute to pharyngeal organs and to the connective, skeletal, neural and vascular tissues of the head and neck.

Congenital adrenal hyperplasia

A condition that is in most cases due to CYP21 deficiency, and is characterized by the deficiency in the hormones cortisol and aldosterone and an overproduction of androgens, which results in ambiguous genitalia in females.

Substantia nigra

A region of the ventral midbrain that contains pigment and sends afferent dopamine-releasing neurons to the striatum.

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Wilhelm, D., Koopman, P. The makings of maleness: towards an integrated view of male sexual development. Nat Rev Genet 7, 620–631 (2006). https://doi.org/10.1038/nrg1903

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