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Mammary Gland Development
Fetal Period


Mammary Gland
Development During the
Fetal Period

Cross section of a beef heifer's udder.

Any mishap in development occurring before birth will influence further development and, ultimately, may affect mammary function and milk production.

Mammary Development Before Birth

The early embryo has three distinguishable layers of cells which ultimately give rise to various tissues and organs of the body. These are: the ectoderm (outer layer) which gives rise to the skin (epidermis) and nervous system; the mesoderm (middle layer) which gives rise to muscle, blood vascular system, and sex organs; and the endoderm (inner layer) which gives rise to the alimentary canal and digestive glands. The mammary gland is derived from the ectoderm and mesoderm layers. The specific description given below (days of fetal age, embryo size, etc.) is for the bovine species, but the general sequence of developmental changes are similar for most mammals.

Mammary Band - The mammary band is found at ~32 days in the bovine embryo (~1 cm long). The mammary band persists for about 1 wk. The mammary band is a broad band of ectodermal cells running on either side of the trunk from the upper limb to the lower limb. The mammary band is called the first anlage of the mammary gland; it is the first discernible cell or group of cells which are destined to form any distinct body part or organ, in this case the mammary gland. Remember that the mammary gland is a skin gland; therefore it makes sense that it is derived from the ectodermal layer. In the human embryo, the mammary band first appears at about 4 mm and is clearly differentiated by about 6 - 8 mm.

This is a 33 day-old bovine embryo (red arrow). This is approximately the time that the trophoblast membranes attach to the endometrium. This embryo has only just formed its mammary band a couple of days previously Bovine embryo with placental membranes.

Mammary Streak - There is further development of the mammary band.

Mammary Lines - The mammary streak becomes further differentiated to form the mammary line by the 4 - 5th wk. of fetal age when the bovine embryo is about 1.4 - 1.7 cm. The mammary line is a narrow ridge of slightly taller ectodermal cells resting on a strip of condensed mesenchymal cells (cells from the mesoderm). This mammary line gradually extends to most of the length of the mammary band area. The mammary lines begin to form on the human embryo at about 7 mm.

Mammary Crest - The mammary lines begin to shorten and the ectodermal cells begin to divide and grow into the mesenchymal cell layer. There remains a distinct basal membrane separating the expanding ectodermal crest structure and the underlying mesoderm. The mammary crest will be recognizable in the areas where the mammary glands will ultimately form; in the inguinal region in the bovine; in the thoracic region in the human embryo.

Mammary Hillock - The ectodermal cells continue an inward growth into the mesenchymal layer. In cross-section, the mammary hillock appears as a dome of ectodermal cells growing into the mesenchymal layer.

Mammary Bud - The ectodermal cells continue to grow into the mesechymal layer, resulting in formation of a spherical or globular structure. In the bovine species there are two mammary buds in the inquinal region on each side on what was the mammary band (these ultimately will give rise to the fore and rear quarters). The mammary bud is formed early in the second month in the bovine when the embryo is about 2.1 cm long. In the human embryo the mammary bud is recognizable at about 20 - 30 mm.

The mammary bud formation is a critical stage in mammary development. It is after the bud forms when several other important processes begin. The ectodermal layers sink into the mesenchyme leaving forming dimple on the embryo's surface (mammary pit). The mammary bud stage marks the beginning of differentiation patterns which distinguish various species. The mammary bud stage also marks the point at which glands of females and males can be distinguished.

Differentiation of the Sexes at the mammary bud stage: Up to the mammary bud stage, males and females develop identically. Differences in mammary development between sexes are recognizable at the mammary bud stage.

    • female mammary buds are ovoid, males are spherical.
    • female mammary buds have a smaller volume than the male's.
    • female mammary buds do not form as deep a mammary pit as the male's.
    • Teat formation in the female is characterized by a fairly pointed tip, male's teat is flat on the end.
    • There is no teat formation in male rats, mice, or horses (see below on the role of steroid hormones in gland differentiation for more on this).
    • In other species, the male mammary development becomes slower than that of the female after the mammary bud stage.

Early teat development - In the bovine the early origins of teat development begin by about 60 days when the fetus is about 8 cm long. Rapid growth of the mesenchyme around the mammary bud raises the area containing the bud up from the surrounding surface. Blood vessels begin to form in the mesenchymal area associated with the bud. Also, an invagination of the mammary bud cells into the mesenchyme occurs, pushing the mesenchymal cells aside. This becomes the primary sprout by 80 days. The primary sprout ultimately gives rise to the gland cistern, but at this early point it is still a solid core of cells.

In the human embryo, from about the third to the fifth month of fetal development, the mammary bud does not change much. At about 5 months, the surface of the mammary bud spreads out and a depression forms at the surface (analogous to the mammary pit in the bovine; see above). In addition, the deep layer of the bud epithelium proliferates and produces about 10 to 25 secondary buds. These secondary buds gradually lengthen and become solid cords of epithelial cells growing into the mesenchymal tissue until they reach the subcutaneous tissue underlying the mesenchymal cells. These secondary buds or epithelial cords will ultimately form the lactiferous ducts. The epithelial cords gradually branch at their ends. Remember from the Mammary Gland Structure Lesson that the human has 10 - 20 or so lactiferous ducts or openings exiting each nipple. Each epithelial cord will correspond to a lactiferous duct or opening at the nipple in the developed gland.

In the mouse embryo, only one epithelial cord grows from the mammary bud. This is called the primary mammary cord and will give rise to the lactiferous sinus. Remember from the Mammary Gland Structure Lesson that the mouse has only one lactiferous duct or opening exiting each nipple.

Secondary Sprouts - In the bovine fetus, the secondary sprouts branch from the primary sprout at about 13 - 14 wks, just prior to canalization of the primary sprout. Secondary sprouts are still a solid core of cells at this time. The secondary sprouts will form the major ducts leading to the major lobes of the gland.

Canalization - The process of forming a lumen in the solid core of epithelial cells in the primary and secondary sprouts is called canalization and begins at about 100 days in the bovine fetus (about 19 cm long). As the circumference of the sprout increases, a lumen is formed. This begins at the proximal end of the primary sprout (inner end) and proceeds in both directions, forming the gland cistern first. The secondary sprouts begin to open at the base. Canalization proceeds back toward the surface, forming the teat cistern (at about 130 days), and finally the streak canal. Expansion and canalization continue until canals are lined with only a couple of layers of epithelial cells.


Other aspects of development of the fetal mammary gland

As the teat develops, the tip invaginates from the outside, and the surface cells become cornified and skin-like, resulting in formation of the streak canal. This ultimately forms the keratin lining of the streak canal. When the bovine fetus is about 8 - 12 cm, the mesenchymal cells develop into connective tissue components with fibrous threads developing perpendicular to the base of the udder, as well as forming blood vessels and the lymph system. At 12 - 13 cm in the bovine fetus, the connective tissue cells (from the mesenchyme) form whorls that give rise to the nonsecretory connective tissue and fat. Part of the median suspensory ligament is formed by the time the bovine fetus is 60 cm.

Development of udder shape, including fat pad, begins at about 2 - 3 mos. of fetal age in the bovine. Distinct differences between individuals can be observed at this time. The size of the fat pad and its subsequent development are important for ultimate mammary parenchymal tissue development. Limiting development of the fat pad may limit parenchymal development after birth (see Faulkin, L.J. and K.B. DeOme. 1960. Regulation of growth and spacing of gland elements in the mammary fat pad of the C3H mouse. J. Natl. Cancer Inst. 24:953; Williams, R. and C. W. Turner. 1961. Effect of increased levels of ovarian hormones and duration of treatment on teh experimental induction of growth of the cows udder. J. Dairy Sci. 44:524; and Johnsson, I.D., I.C. Hart, and A. Turvey. 1986. Pre-pubertal mammogenesis in the sheep. 3. The effects of restricted feeding or daily administration of bovine grwoth hormone and bromocriptine on mammary growth and morphology. Anim. Prod. 45:53).

Note that the fat pad precursor develops from the more deep subcutaneous mesenchymal cells, while the connective tissue or mesenchymal tissues associated with the mammary parenchymal tissue develop from the mesenchyme adjacent to the parenchyma (see Sakakura, 1987, or Cunha and Hom, 1996, from the list above).


Most of the major developmental changes that will occur before birth have occurred by mid-gestation.

At Birth - the following are observed:

  • Teats are well developed.
  • Secondary sprouts are canalized, but still have the solid core of cells at the end. These are the cells that continue to grow and branch.
  • Growth of the sprouts is limited to the area around the gland cistern. Only a few tertiary sprouts are present.
  • Nonsecretory tissue is well formed (connective tissue, blood vessels, lymph vessels).
  • The male gland is similar to the female, but not as fully developed.
  • Secretory or glandular parts are not developed at this time.

Role of steroid hormones in mammary development during the fetal stage

See for more detail: Raynaud, A., 1961.

Remember from above that male mice have no nipples. In male mouse fetuses, rather than the primary mammary cord forming after mammary bud formation, the mesenchymal tissue underlying the mammary bud becomes thickened with a dense layer of mesenchymal cells. The mammary bud is actually exteriorized, becomes separated from the epidermis, and is eliminated. As a result, no nipple or mammary structures are present in the newborn male mouse. Thus, the male pattern (masculinization) of mammary development is indicated at birth of the mouse fetus as the absence of nipples and the female pattern is indicated by the presence of nipples. Androgen receptors appear in the developing mouse mammary gland at the early bud stage and the production of androgen by the developing male testis has a role in the masculinization of the developing mammary gland.

The developmental pattern of mammary glands in the mouse fetus has been used to study the role of steroid hormones in mammary development during the fetal stage. The following examples are from studies using mice where the steroid hormone exposure of the developing fetus is experimentally manipulated. Remember that pregnancy in mice is 21 days.

Testosterone injection into the pregnant mouse on days 8, 9, or 10 of pregnancy leads to masculinization of the mammary gland of female fetuses. The female fetuses are born without nipples. The mammary anlage (here the mammary bud) becomes exteriorized and is separated from the epidermis, as observed by day 14 or 15. Mammary development of male fetuses are not further affected by the testosterone treatment of the mother.

Gonadectomy of male fetuses results in the female mammary developmental pattern in the male fetuses. This has been done by localized irradation on day 13 of pregnancy of the region where the gonads form in the mouse fetuses. This functionally castrates the fetus. By day 18 of pregnancy, the mammary development of the male mice included formation of normal primary mammary cords. Gonadectomy of the female fetus by irradiation does not alter normal mammary development.

Injection of high doses of estrogens into the female fetuses or into the mother results in a number of abnormalities of mammary development. These abnormalities include total suppression of development of the mammary anlage (bud) leaving only a nipple with no internal structures; partial inhibition of the mammary bud; formation of a cavity at the site of the mammary bud; abnormally shaped mammary buds; formation of multiple primary mammary cords; excessive formation of the mesenchyme around the primary mammary duct.

Injection of growth hormone into the mouse fetus increases the size of the developing mammary gland in both male and female fetuses, suggesting that this hormone is also involved in development of the mammary gland during the fetal stage.


 
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