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Integrated morphodynamic signalling of the mammary gland

Key Points

  • The mammary gland is a unique organ that executes most of its development postnatally. At the onset of puberty, the tips of the rudimentary gland present at birth are transformed into terminal end buds, which are induced by endocrine, paracrine and autocrine signals to repeatedly elongate and bifurcate to generate a full epithelial ductal tree.

  • A subset of regulatory molecules, including fibroblast growth factor receptors and matrix metalloproteinases, exhibit location-dependent activity and expression patterns within the gland, thereby providing local morphogenetic control.

  • The fundamental mechanisms that govern the localized expression and activity of key regulators are unclear. Tissue microfabrication approaches have suggested that the geometry of the gland may itself template morphogenesis by forming spatial gradients in chemical and mechanical signals.

  • Real-time imaging of developing mammary organoids has revealed large-scale coordinated epithelial cell movements during morphogenesis. These rapid rearrangements might serve to establish the regional differences in molecular regulators that drive morphogenesis. The cellular plasticity of the developing mammary epithelium might be enabled by expression of genes classically associated with epithelial–mesenchymal transition.

  • Epithelial–stromal crosstalk is a key aspect of mammary morphogenesis. The various cell types that comprise the mammary fat pad communicate signals with the developing epithelium and with each other to control morphogenesis.

  • Mammary morphogenesis is thus a complex process that requires the integration of diverse chemical and physical signals from several different cell types and over several length scales. To fully understand how these cues cooperate to give rise to the final architecture of the gland, more detailed expression and function studies are needed. Quantitative computational and culture models are likely to be helpful in answering questions that are not readily addressable in vivo.

Abstract

The mammary gland undergoes a spectacular series of changes as it develops, and maintains a remarkable capacity to remodel and regenerate for several decades. Mammary morphogenesis has been investigated for over 100 years, motivated by the dairy industry and cancer biologists. Over the past decade, the gland has emerged as a major model system in its own right for understanding the cell biology of tissue morphogenesis. Multiple signalling pathways from several cell types are orchestrated together with mechanical cues and cell rearrangements to establish the pattern of the mammary gland. The integrated mechanical and molecular pathways that control mammary morphogenesis have implications for the developmental regulation of other epithelial organs.

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Figure 1: The mammary gland undergoes distinct stages of remodelling during development.
Figure 2: Multiple integrated signalling networks regulate mammary morphogenesis during puberty.
Figure 3: Potential modes of mechanotransduction in the developing mammary gland.
Figure 4: Interactions between diverse cell types of the stroma coordinate mammary morphogenesis.

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Acknowledgements

We apologize to colleagues whose work could not be discussed owing to space limitations. The authors are supported by grants from the US National Institutes of Health (CA128660, HL110335 and GM083997), Susan G. Komen for the Cure (FAS0703855), the David & Lucile Packard Foundation and the Alfred P. Sloan Foundation. C.M.N. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.

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Glossary

Adipocytes

Also known as fat cells. Adipocytes contain one or more lipid droplets and comprise the body's adipose tissue.

Placodes

Epithelial thickenings in the embryo that give rise to an organ.

Chemotactic gradients

Chemical gradients that influence the directional motion of cells in the process of chemotaxis.

Organoids

Multicellular structures that resemble organs in architecture and function.

Paracrine signalling

A form of cell signalling in which a signal released by one cell elicits an effect within a nearby cell.

Endocrine signalling

A form of cell signalling in which a hormonal signal released by an endocrine gland elicits an effect within a distant cell.

Primary cilia

Long, slender sensory organelles that project from eukaryotic cells and are composed of a microtubule-based cytoskeleton.

MicroRNA

Small non-coding RNA molecules that regulate gene expression at the post-transcriptional level.

Autocrine signalling

A form of cell signalling in which a signal released by a given cell elicits an effect within the same cell.

Morphogen

A chemical signal that forms a concentration gradient and mediates pattern formation during tissue development.

Microfabrication

The process of fabricating micrometre-sized structures. Used in biomedical research to control the size, shape and spatial arrangement of proteins, cells and tissues.

Mechanical stress

A physical quantity defined as force per unit area.

Mechanotransduction

The phenomenon whereby cells interpret mechanical signals and transform them into a biochemical response, such as signalling or changes in gene expression.

Collective migration

The process in which cells move as a group, without dissolving cell–cell junctions.

Lateral inhibition

The signalling process through which a group of cells reduces the activity of an adjacent group.

Tensile forces

Forces that tend to extend a body.

Directional persistence

The tendency of a cell to move in a straight line.

Angiogenesis

The formation of new blood vessels from existing ones.

Macrophages

A type of blood cell that mediates the body's immune response by ingesting foreign material, including pathogens.

Eosinophils

A type of blood cell that mediates the body's immune response by producing chemical agents to combat multicellular pathogens.

Mast cells

A type of cell that is considered to be part of the immune response. Mast cells contain granules rich in histamine and heparin and mediate the body's inflammatory and allergic responses.

Niche

The microenvironment in which stem cells reside, characterized both in terms of location within a tissue and function. The niche is responsible for directing the maintenance, renewal and differentiation of stem cells.

Acinar

A berry-shaped cluster of cells.

Bipotent

The ability to give rise to two types of differentiated cells.

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Gjorevski, N., Nelson, C. Integrated morphodynamic signalling of the mammary gland. Nat Rev Mol Cell Biol 12, 581–593 (2011). https://doi.org/10.1038/nrm3168

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