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First published online February 22, 2008
doi: 10.1242/10.1242/dev.005439

Development 135, 995-1003 (2008)
Published by The Company of Biologists 2008
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Mammary development in the embryo and adult: a journey of morphogenesis and commitment

Christine J. Watson* and Walid T. Khaled

Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.


Figure 1
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  		Fig. 1. Embryonic mammary gland development. (A,B) Diagram of an E10.5 mouse embryo (A) showing the position of the milk line (dashed line between limbs), and of an E12.5 mouse embryo (B) showing the positions of the five pairs of mammary placodes, which become mammary buds (MB1-5) along the anteroposterior axis (MB1 and MB5 are hidden by the limb buds and only one flank is shown). (C) Overview of mouse embryonic mammary gland development. Placodes, which are visible at E11.5, transform into bulbs of epithelial cells, which sink into the underlying mesenchyme at E13.5 to become the mammary buds. The mesenchymal cells (orange) that surround the buds condense to become the mammary mesenchyme (grey). By E15.5, these buds elongate to form sprouts, which develop a lumen with an opening to the skin, marked by the formation of the nipple sheath. As the end of pregnancy approaches, at E18.5, the sprouts become small arborized glands that invade what has now become the fat pad (buff). Development is essentially arrested at this stage until puberty.

 

Figure 2
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  		Fig. 2. Induction of bud outgrowth. Cross-section of an embryonic mouse mammary bud at E13.5-15.5. PTHrP and BMP signalling interact to initiate mammary bud outgrowth and nipple formation. PTHrP, which is secreted from mammary epithelial cells of the mammary bud, increases BMPR1A expression in the mammary mesenchymal cells (purple shading), which can now respond to BMP4. This triggers epithelial outgrowth, elevates MSX2 expression, and inhibits hair follicle formation within the nipple sheath. Modified with permission from Hens et al. (Hens et al., 2007Go).

 

Figure 3
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  		Fig. 3. Adult mouse mammary gland development. A schematic of the stages (A-F) of mammary gland development in the adult mouse, from pre-puberty through to pregnancy, lactation and involution. Some of the important factors in these developmental processes are highlighted. LN, lymph node; TEB, terminal end bud.

 

Figure 4
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  		Fig. 4. Signalling in T cell lineage commitment. Multiple pathways are implicated in T helper type 2 (Th2) cell differentiation. Importantly, IL4/13 signalling through STAT6 induces the transcription of IL4R{alpha} and GATA3, which is the master regulator of Th2 differentiation. GATA3, along with other transcription factors, STAT6, STAT5 and c-MAF, induce the transcription of IL4, IL5 and IL13. GATA3 is also activated by the Notch pathway independently of STAT6 activity, providing an explanation for GATA3 expression in Stat6-null mice. The balance between different members of the nuclear factor of activated T-cells (NFAT) family of transcription factors also plays a role in the transcription of IL4 and Th2 differentiation. P, phosphorylation; TACE (ADAM17); ICD, intracellular domain.

 

Figure 5
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  		Fig. 5. The IL4/13-STAT6-GATA-3 pathway in mammary gland development. A summary of recent findings that identify the IL4/13-STAT6-GATA3 pathway as being an important regulator of mammary gland development and lineage commitment.

 

Figure 6
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  		Fig. 6. Lineage committment in mammary progenitor cells. (A) A mammary stem cell (blue) in its niche (purple). (B) Stem cells self-renew in their niche in a process that might require GATA3. Asymmetrically dividing stem cells produce transit-amplifying (light blue) daughter cells that commit to either the basal or luminal progenitor lineages. A common progenitor for ductal and alveolar cells is depicted, although there might be two different progenitors. Induction of STAT6 in response to IL4 and IL13 induces further expression of GATA3 and possibly of c-MAF, which are required for differentiation to alveolar cells. RBPJ{kappa} is required to maintain the alveolar phenotype and suppresses differentiation along the basal lineage.

 

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© The Company of Biologists Ltd 2008