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Cooperation of signalling pathways in embryonic mammary gland development

Nature Reviews Genetics volume 8, pages 963–972 (2007)Cite this article

A Corrigendum to this article was published on 03 June 2008

Key Points

  • Mammary glands are the defining feature of mammals. They develop as derivatives of the ventral skin, along two symmetrical lines along the ventral surface of the embryo.

  • Initiation of the epithelial bud and ductal outgrowth is coordinated through short-range signalling between epithelium and mesenchyme. Studies of natural and induced mouse mutants in which early mammary development is perturbed have identified genetic networks that regulate specific steps in this process.

  • Research in early mammary development is largely aimed at: understanding how mammary cell identity is determined; identifying the signals that induce the development of the mammary bud precursors in reproducible positions along the body axes, and mediate the exchange between epithelium and mesenchyme; and establishing which downstream targets transmit these signals.

  • The site where future mammary glands develop is called the milk line. Factors such as fibroblast growth factor (FGF), wingless-related MMTV integration site (WNT) and neuregulin 3 (NRG3), which emanate from somites and the lateral mesoderm, form gradients that determine the position of the milk line.

  • Cells in the milk line assume mammary cell identity and form small placodes that develop into buds that elongate and sprout into a ductal tree.

  • The transcription factors lymphoid enhancer-binding factor 1 (LEF1) and T-box 3 (TBX3) are required for placode development. In the absence of these proteins milk-line-specific gene expression is induced but further development is arrested.

  • Mammary epithelial cells in the placode induce the formation of mammary mesenchyme cells in their vicinity by signalling through the parathyroid hormone-like hormone (PTHLH). These mesenchymal cells promote mammary cell identity.

  • Mammary epithelial cells maintain their identity by suppressing hedgehog signalling that is mediated by Gli-Kruppel family member 3 (GLI3). Initiation of hedgehog signalling causes mammary epithelial cells to revert to an epidermal fate.

  • Ductal outgrowth requires the activities of PTHLH and RASGRF1 (Ras protein-specific guanine-releasing factor 1). Bone morphogenetic protein 4 (BMP4) and insulin-like growth factor 1 (IGF1) mediate this process.

  • Many of the signalling pathways that are involved in early mammary gland development are deregulated in breast cancer and in other disorders. A better understanding of the role of these pathways in normal development will therefore be of great importance for understanding many human diseases.

Abstract

Mammary glands become functional only in adult life but their development starts in the embryo. Initiation of the epithelial bud and ductal outgrowth are coordinated through short-range signals between epithelium and mesenchyme. Studies of natural and induced mouse mutants in which early mammary development is perturbed have identified genetic networks that regulate specific steps in these processes. Some of these signals contribute to aberrant mammary development in humans and are deregulated in cancer.

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Figure 1: Morphological stages in the embryonic development of the mammary gland.
Figure 2: Signalling molecules that regulate mammary line initiation and placode formation.
Figure 3: Signalling molecules that regulate dorso-lateral positioning of the mammary bud and formation of the dense mammary mesenchyme.
Figure 4: Regulatory networks in the early mammary gland.

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Acknowledgements

The author is supported by the intramural programme of The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH).

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  1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8, Room 101, 8 Center Drive, Bethesda, 20892–20822, Maryland, USA

    Gertraud W. Robinson

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DATABASES

OMIM

Blomstrand chondrodysplasia

FURTHER INFORMATION

Laboratory of Genetics and Physiology at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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Glossary

Ectoderm

The outer germ layer that covers the early embryo.

Mesenchyme

The layer of embryonic connective tissue that lies between the endoderm and the ectoderm. It gives rise to connective tissue, muscles and skeletal structures.

Anlage

The embryonic rudiment of an organ.

Placode

A lens-shaped thickening of the surface ectoderm that is the precursor of the mammary bud.

Ulnar mammary syndrome

A developmental disorder that is characterized by abnormalities in limbs and apocrine glands.

Primary sprout

A short duct that is formed when the mammary bud elongates at the tip and pushes through the mammary mesenchyme.

Hypohidrotic ectodermal dysplasias

A group of diseases that are characterized by defects in the development of the ectoderm; they affect skin, hair, teeth, nails and apocrine glands.

Mammary mesenchyme

A layer of mesenchymal cells that surround the mammary bud.

Axilla

The junction between forelimb and main body.

Mammary or milk line

A region along the flank of the embryo that shows responsiveness to form mammary placodes when it is exposed to inducing signals.

Fat pad

The stromal compartment of the mammary gland; it is composed of adipocytes and fibroblasts.

Planar cell polarity

The coordinated organization of cells within the plane of a single layer of cells.

Somite

Aggregates of mesodermal cells that are positioned on both sides of the neural tube in the early embryo. They give rise to the vertebrae, skeletal muscle and the dermis (the layer of connective tissue that underlies the epidermis).

Dermamyotome

The part of the somite that develops into dermis and muscle.

Haploinsufficiency

A gene dosage effect that occurs when a diploid requires both functional copies of a gene for a wild-type phenotype. An organism that is heterozygous for a haploinsufficient locus does not have a wild-type phenotype.

Penetrance

The proportion of individuals with a specific genotype who manifest the genotype at the phenotypic level. If penetrance of a disease allele is 100% then all individuals carrying that allele will express the associated disorder.

Humoral hypercalcaemia of malignancy

The presence of a high concentration of calcium ions in the blood of cancer patients.

Cell autonomous

The effect of a mutation is said to be cell autonomous when it affects the cell in which the mutated gene is expressed.

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Robinson, G. Cooperation of signalling pathways in embryonic mammary gland development. Nat Rev Genet 8, 963–972 (2007). https://doi.org/10.1038/nrg2227

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