Embryonic Mammary Gland Development

Abstract

Mammary glands are derived from the ectoderm and are a defining feature of mammals. The number of glands that develop along the ‘mammary lines’ on either side of the ventral trunk depends on the mammalian species. The mesoderm specifies the position in which glands develop. Positional information is encoded by transcription factors and transmitted to overlying ectoderm by signalling molecules. Determination of the mammary epithelium arises from induction of transcription factors and signalling molecules. Signals from the mammary epithelium induce the underlying mesoderm to form the mammary mesenchyme required for further development. The gland initiates as a discrete placode which sinks into the mesoderm to form a bud; the bud then lengthens to form an elongated sprout, which undergoes branching morphogenesis in a pattern dictated by the mesoderm. The gland lining is generated by formation of the lumen, and bipotent mammary stem cells give rise to luminal epithelial and myoepithelial cells.

Key Concepts

  • Mammary glands develop along ‘mammary lines’ that run from axilla (anterior) to groin (posterior) along both right and left sides of the ventral aspect of the mammalian trunk.
  • Ectoderm cells of the mammary line migrate and aggregate to form individual discrete mammary placodes.
  • The precise location of the mammary line and the placodes in the ectoderm is controlled by signals from underlying mesodermal tissues.
  • Signals that control the formation of the mammary line and placodes include members of the WNT, FGF, NEUREGULIN and BMP signalling pathways. The Hedgehog signalling pathway is also involved.
  • The TBX3 transcription factor is essential for the formation of the mammary placodes in mouse embryos, and mutations in the TBX3 gene have been found in patients with Ulnar‐mammary syndrome.
  • The epithelial cells of the mammary bud produce parathyroid hormone‐related protein, which induces nearby mesoderm to form the mammary mesenchyme.
  • Interactions between the mammary epithelial cells and the mammary mesenchyme are essential for further development and the subsequent elongation of the mammary bud to form a mammary sprout, which then undergoes branching morphogenesis in a pattern dictated by the deeper mesenchyme.
  • Formation of the lumen of the embryonic gland involves fusion of microlumina created by local development of nonadhesive surfaces on the mammary epithelial cells and generates the epithelial lining which consists of an inner layer of luminal cells and an outer layer of myoepithelial cells.
  • The cells of the mammary placode are determined to give rise to mammary epithelial cells; in the mammary bud, mammary stem cells can be detected that can give rise to both luminal and myoepithelial cells.
  • Parallels, such as invasiveness, exist between the development of embryonic mammary glands and breast tumours and many of same molecules are involved.

Keywords: ectoderm; mammary gland; mouse embryo; positional information; induction; epithelial–mesenchymal interactions; mammary stem cells; branching morphogenesis; invasiveness

Figure 1. (a) Diagrams showing the location of the ‘mammary line’ and mammary buds in E10.5 and E12.5 mouse embryos respectively. Pale blue indicates ectoderm, dark blue the mammary line and M the mammary bud (green). (b–f) Stages in embryonic development of the mouse mammary gland shown in transverse sections of the trunk. Scale bars represent 100 µm in each case. (b) ‘Mammary line’ (arrowed; base of ectoderm indicated by dotted line), E11.25 mouse embryo. (c) Mammary placode (base of ectoderm indicated by dotted line), E11.75 mouse embryo. (d) Early mammary bud, E12.5 mouse embryo. (e) Late mammary bud (mammary bulb), E14.5 mouse embryo. (f) Branching and lumen formation of an E17–18 mouse embryo, section shows the region that will form the primary duct.
Figure 2. Diagrams summarising the regulatory molecular networks involved in specifying the mammary line and in the formation of the mammary placodes. (a) Longitudinal section of trunk showing specification along the anteroposterior axis; (b) transverse section of trunk showing specification across the dorsoventral axis. (a) Section through anterior trunk and somites 14–16 only for clarity and specification of both mammary line (dark blue) and mammary placode 3 (MP3; green). Mesoderm coloured brown. Details of regulatory molecular interactions in the ventral tip of the somites, the mammary line and the mammary placode are shown in black boxes. RA, retinoic acid. Dotted orange arrows indicate mesenchymal signalling to ectoderm. Solid arrows indicate positive regulation which may be direct or indirect. (b) Section through MP3; colours and arrows as above. Ectoderm coloured pale blue. Black barred lines indicate negative regulation. Pink dots indicate dorsoventral BMP4 gradient.
Figure 3. Diagram summarising the regulatory molecular networks mediating epithelial–mesenchymal interactions in the mammary bud shown in transverse section. Colour coding as in Figure. Mammary mesenchyme coloured dark brown. Dotted arrows indicate signalling between mammary mesenchyme and mammary epithelium. Solid arrows indicate positive regulation. Pink dots indicate dorsoventral BMP4 gradient.
Figure 4. Diagrams summarising the regulatory molecular networks governing branching morphogenesis (a) and illustrating formation of the lumen (b) shown in transverse sections. Colour coding as in Figure. Deep mesenchyme (presumptive fat pad) coloured mauve.
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References

Asselin‐Labat ML, Sutherland KD, Barker H, et al. (2007) Gata‐3 is an essential regulator of mammary‐gland morphogenesis and luminal‐cell differentiation. Nature Cell Biology 9: 201–209.

Bamshad M, Lin RC, Law DJ, et al. (1997) Mutations in human TBX3 alter limb, apocrine and genital development in ulnar‐mammary syndrome. Nature Genetics 16: 311–315.

Ballim RD, Mendelsohn C, Papaioannou VE and Prince S (2012) The ulnar‐mammary syndrome gene, Tbx3, is a direct target of the retinoic acid signalling pathway, which regulates its expression during mouse limb development. Molecular Biology of the Cell 23: 2362–2372.

Boras‐Granic K, Chang H, Grosschedl R and Hamel PA (2006) Lef1 is required for the transition of Wnt signalling from mesenchymal to epithelial cells in the mouse embryonic mammary gland. Developmental Biology 295: 219–231.

Boras‐Granic K, Dann P and Wysolmerski JJ (2014) Embryonic cells contribute directly to the quiescent stem cell population in the adult mouse mammary gland. Breast Cancer Research 16: 487.

Carroll LS and Capecchi MR (2015) Hoxc8 initiates an ectopic mammary program by regulating Fgf10 and Tbx3 expression and Wnt/bcatenin signalling. Development 142: 4056–4067.

Cho K‐Y, Kim J‐Y, Song S‐J, et al. (2006) Molecular interactions between Tbx3 and Bmp4 and a model for dorso‐ventral positioning of mammary gland development. Proceedings of the National Academy of Sciences 103: 16788–16793.

Cho KW, Kwon HJ, Shin JO, et al. (2012) Retinoic acid signalling and the initiation of mammary gland development. Developmental Biology 365: 259–266.

Chu EY, Hens J, Andl T, et al. (2004) Canonical WNT signalling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131: 4819–4829.

Cunha GR and Hom YK (1996) Role of mesenchymal‐epithelial interactions in mammary gland development. Journal of Mammary Gland Biology and Neoplasia 1: 21–35.

Davenport TG, Jerome‐Majewska LA and Papaioannou VE (2003) Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 130: 2263–2273.

Douglas NC and Papaioannou VE (2013) The T‐box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. Journal of Mammary Gland Biology and Neoplasia 18: 143–147.

Eblaghie MC, Song S‐J, Kim JY, et al. (2004) Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos. Journal of Anatomy 205: 1–13.

Heckman BM, Chakravarty G, Vargo‐Gogola T, et al. (2007) Crosstalk between the p190‐B RhoGAP and IGF signalling pathways is required for embryonic mammary bud development. Developmental Biology 309: 137–149.

Hens JR, Dann P, Zhang JP, et al. (2007) BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction. Development 134: 1221–1230.

Hiremath M and Wysolmerski J (2013) Parathyroid hormone‐related protein specifies the mammary mesenchyme and regulates embryonic mammary development. Journal of Mammary Gland Biology and Neoplasia 18: 171–177.

Hogg N, Harrison C and Tickle C (1983) Lumen formation in the developing mouse mammary gland. Journal of Embryology and Experimental Morphology 73: 39–57.

Howard B, Panchal H, McCarthy A and Ashworth A (2005) Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification. Genes and Development 19: 2078–2090.

Howard B and Ashworth A (2006) Signalling pathways implicated in early mammary gland morphogenesis and breast cancer. PLoS Genetics 2: e112.

Jerome‐Majewska LA, Jenkins GP, Ernstoff E, et al. (2005) Tbx3, the ulnar‐mammary syndrome gene, and Tbx2 interact in mammary gland development through a p19Arf/p53‐independent pathway. Developmental Dynamics 234: 922–933.

Jung H‐S, Francis‐West PH, Widelitz RB, et al. (1998) Local inhibitory action of the BMPs and their relationships with activators in feather formation: implications for periodic patterning. Developmental Biology 196: 11–23.

Kratochwil K (1969) Organ specificity in mesenchymal induction demonstrated in the embryonic development of the mammary gland of the mouse. Developmental Biology 20: 46–71.

Kratochwil K and Schwartz P (1976) Tissue interaction in androgen response of embryonic mammary rudiment of mouse: identification of target tissue for testosterone. Proceedings of the National Academy of Sciences of the United States of America 73: 4041–4044.

Lee MY, Sun L and Veltmaat JM (2013) Hedgehog and Gli signalling in embryonic mammary gland development. Journal of Mammary Gland Biology and Neoplasia 18: 133–138.

Lee JM, Cho KW, Kim EJ, et al. (2015) A contrasting function for miR‐137 in embryonic mammogenesis and adult breast carcinogenesis. Oncotarget 6: 22048–22059.

Lindfors PH, Voutilainen M and Mikkola ML (2013) Ectodysplasin/NF‐κB signalling in embryonic mammary gland development. Journal of Mammary Gland Biology and Neoplasia 18: 165–169.

Mailleux AA, Spencer‐Dene B, Dillon C, et al. (2002) Role of FGF10/FGFR2b signalling during mammary gland development in the mouse. Development 130: 53–60.

Makarem M, Spike BT, Dravis C, et al. (2013) Stem cells and the developing mammary gland. Journal of Mammary Gland Biology and Neoplasia 18: 209–219.

Mills AA, Zheng B, Wang X‐J, et al. (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398: 708–713.

Mustonen T, Ilmonen M, Pummila M, et al. (2004) Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 131: 4907–4919.

Oftedal OT and Dhouailly D (2013) Evo‐devo of the mammary gland. Journal of Mammary Gland Biology and Neoplasia 18: 105–120.

Panchal H, Wansbury O, Parry S, Ashworth A and Howard B (2007) Neuregulin3 alters cell fate in the epidermis and mammary gland. BMC Developmental Biology 7: 105.

Phippard DJ, Weber‐Hall SJ, Sharpe PT, et al. (1996) Regulation of Msx‐1, Msx‐2, Bmp‐2 and Bmp‐4 during foetal and postnatal mammary gland development. Development 122: 2729–2737.

Propper AY (1978) Wandering epithelial cells in the rabbit embryo milk line. A preliminary scanning electron microscope study. Developmental Biology 67: 225–231.

Propper AY, Howard BA and Veltmaat JM (2013) Prenatal morphogenesis of mammary glands in mouse and rabbit. Journal of Mammary Gland Biology and Neoplasia 18: 93–104.

Sakakura T, Nishizuka Y and Dawe CJ (1976) Mesenchyme‐dependent morphogenesis and epithelium‐specific cytodifferentiation in mouse mammary gland. Science 194: 1439–1441.

Sakakura T, Nishizuka Y and Dawe CJ (1979) Capacity of mammary fat pads of adult C3H/HeMs mice to interact morphogenetically with fetal mammary epithelium. Journal of the National Cancer Institute 63: 733–736.

Sakakura T, Sakagami Y and Nishizuka Y (1982) Dual origin of mesenchymal tissues participating in mouse mammary gland development. Developmental Biology 91: 202–207.

Satokata I, Ma L, Ohshima H, et al. (2000) Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nature Genetics 24: 391–395.

Shackleton M, Vaillant F, Simpson KJ, et al. (2006) Generation of a functional mammary gland from a single stem cell. Nature 439: 84–88.

Spike BT, Engle DD, Lin JC, et al. (2012) A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer. Cell Stem Cell 10: 183–197.

Tlsty TD (2007) Luminal cells GATA have it. Nature Cell Biology 9: 135–136.

Van Bokhoven H, Hamel BC, Bamshad M, et al. (2001) p63 gene mutations in EEC syndrome, limb‐mammary syndrome, and isolated split hand‐foot malformation suggest a genotype‐phenotype correlation. American Journal of Human Genetics 69: 481–492.

Van den Akker E, Fromental‐Ramain C, de Graaf W, et al. (2001) Axial skeletal patterning in mice lacking all paralogous group 8 genes. Development 128: 1911–1921.

Van Genderen C, Okamura RM, Fariñas I, et al. (1994) Development of several organs that require inductive epithelial‐mesenchymal interactions is impaired in LEF‐1 deficient mice. Genes and Development 8: 2691–2703.

Van Keymeulen A, Rocha AS, Ousset M, et al. (2011) Distinct stem cells contribute to mammary gland development and maintenance. Nature 479: 189–193.

Veltmaat JM, van Veelen W, Thiery J‐P, et al. (2004) Identification of the mammary line in mouse by Wnt10b expression. Developmental Dynamics 229: 349–356.

Veltmaat JM, Relaix F, Le LT, et al. (2006) Gli3‐mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 133: 2325–2335.

Voutilainen M, Lindfors PH, Lefebvre S, et al. (2012) Ectodysplasin regulates hormone‐independent mammary ductal morphogenesis via NF‐κB. Proceedings of the National Academy of Sciences of the United States of America 109: 5744–5749.

Voutilainen M, Lindfors PH, Trela E, et al. (2015) Ectodysplasin/NF‐κB Promotes Mammary Cell Fate via Wnt/β‐catenin Pathway. PLoS Genetics 11: e1005676.

Weil M, Itin A and Keshet E (1995) A role for mesenchyme‐derived tachykinins in tooth and mammary gland morphogenesis. Development 121: 2419–2428.

Yang A, Schweitzer R, Sun D, et al. (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398: 714–718.

Further Reading

Brisken C and O'Malley B (2010) Hormone action in the mammary gland. Cold Spring Harbor Perspectives in Biology 2: a003178.

Inman JL, Robertson C, Mott JD, et al. (2015) Mammary gland development: cell fate specification, stem cells and the microenvironment. Development 142: 1028–1042.

Macias H and Hinck L (2012) Mammary gland development. Wiley Interdisciplinary Reviews: Developmental Biology 1: 533–557.

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Tickle, Cheryll, and Jung, Han‐Sung(Nov 2016) Embryonic Mammary Gland Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026057]