RESUMO
Embryonic mammary gland development involves the formation of mammary placodes, invagination of flask-shaped mammary buds and development of miniature bi-layered ductal trees. Currently there is a good understanding of the factors that contribute to ectodermal cell movements to create these appendages and of pathways that lead to mammary specification and commitment. Gene expression profiles of early bipotent mammary stem cells populations as well as cell surface proteins and transcription factors that promote the emergence of unipotent progenitors have been identified. Analyses of these populations has illuminated not only embryonic mammary development, but highlighted parallel processes in breast cancer. Here we provide an overview of the highly conserved pathways that shape the embryonic mammary gland. Understanding the dynamic signaling events that occur during normal mammary development holds considerable promise to advance attempts to eliminate cancer by restoring differentiative signals.
Assuntos
Glândulas Mamárias Animais , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Animais , Modelos Animais de Doenças , Feminino , Humanos , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , CamundongosRESUMO
Pregnancy and lactation are reproductive processes that rely on physiological adaptations that should be timely and adequately triggered to guarantee both maternal and fetal health. Pineal melatonin is a hormone that presents daily and seasonal variations that synchronizes the organism's physiology to the different demands across time through its specific mechanisms and ways of action. The reproductive system is a notable target for melatonin as it actively participates on reproductive physiology and regulates the hypothalamus-pituitary-gonads axis, influencing gonadotropins and sexual hormones synthesis and release. For its antioxidant properties, melatonin is also vital for the oocytes and spermatozoa quality and viability, and for blastocyst development. Maternal pineal melatonin blood levels increase during pregnancy and triggers the maternal physiological alterations in energy metabolism both during pregnancy and lactation to cope with the energy demands of both periods and to promote adequate mammary gland development. Moreover, maternal melatonin freely crosses the placenta and is the only source of this hormone to the fetus. It importantly times the conceptus physiology and influences its development and programing of several functions that depend on neural and brain development, ultimately priming adult behavior and energy and glucose metabolism. The present review aims to explain the above listed melatonin functions, including the potential alterations observed in the progeny gestated under maternal chronodisruption and/or hypomelatoninemia.
Assuntos
Desenvolvimento Fetal/fisiologia , Lactação/fisiologia , Melatonina/metabolismo , Glândula Pineal/metabolismo , Animais , Feminino , Humanos , Glândulas Mamárias Humanas/embriologia , Sistema Nervoso/embriologia , GravidezRESUMO
The mammary gland is a unique tissue and the defining feature of the class Mammalia. It is a late-evolving epidermal appendage that has the primary function of providing nutrition for the young, although recent studies have highlighted additional benefits of milk including the provision of passive immunity and a microbiome and, in humans, the psychosocial benefits of breastfeeding. In this Review, we outline the various stages of mammary gland development in the mouse, with a particular focus on lineage specification and the new insights that have been gained by the application of recent technological advances in imaging in both real-time and three-dimensions, and in single cell RNA sequencing. These studies have revealed the complexity of subpopulations of cells that contribute to the mammary stem and progenitor cell hierarchy and we suggest a new terminology to distinguish these cells.
Assuntos
Desenvolvimento Embrionário/fisiologia , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Organogênese/fisiologia , Animais , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Embrião de Mamíferos , Células Epiteliais/fisiologia , Feminino , Humanos , Glândulas Mamárias Animais/citologia , Camundongos , Células-Tronco/fisiologiaRESUMO
During early embryogenesis, mammary glands are derived from surface ectoderm and their morphogenesis is controlled by mammary stem cells (MaSCs) and epithelial-mesenchymal transition (EMT). Mammary anlagen stage (E13.5-15.5) is an important stage for fetal mice to achieve EMT dependent mammary morphogenesis. And the characteristics of mammary anlagen repopulating cell population (MaRC) should be identified for understanding its stemness at earlier embryonic stage. Here we quantify and characterize MaSCs proportion at mammary anlagen stage. Compared with adult mouse mammary gland, our data revealed that E14.5 mammary anlagen exhibit higher stem cell activities. Then we purified mammary anlagen cell populations depending on the expression levels of CD24 and CD49f in mouse mammary anlagen, and identified an unique MaRC population (Lin-CD24medCD49f+) by real-time PCR, transplantation and mammosphere forming assays. In addition, by comparing with adult MaSC (Lin-CD24+CD29hi) and differentiated mammary anlagen cells, we find that E14.5 mouse MaRC population exhibit gene expression programs related to mesenchymal properties. To further identify the cell types of E14.5 mouse MaRC population, the expressions of K8, K14, K18, e-cadherin, n-cadherin and vimentin in mammary anlagen Lin-CD24medCD49f + cells were detected by immunofluorescence assay. These findings verified that the undifferentiated E14.5 mouse MaRC population is a heterogeneous population with mesenchymal property, which is associated with cell stemness and mammary duct morphogenesis.
Assuntos
Autorrenovação Celular , Glândulas Mamárias Humanas/citologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Embrionárias Murinas/citologia , Animais , Antígeno CD24/genética , Antígeno CD24/metabolismo , Caderinas/genética , Caderinas/metabolismo , Células Cultivadas , Transição Epitelial-Mesenquimal , Feminino , Humanos , Integrina alfa6/genética , Integrina alfa6/metabolismo , Glândulas Mamárias Humanas/embriologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/fisiologiaRESUMO
Over the past 5 years, several studies have begun to uncover the links between the classical signal transduction pathways and the physical mechanisms that are used to sculpt branched tissues. These advances have been made, in part, thanks to innovations in live imaging and reporter animals. With modern research tools, our conceptual models of branching morphogenesis are rapidly evolving, and the differences in branching mechanisms between each organ are becoming increasingly apparent. Here, we highlight four branched epithelia that develop at different spatial scales, within different surrounding tissues and via divergent physical mechanisms. Each of these organs has evolved to employ unique branching strategies to achieve a specialized final architecture.
Assuntos
Epitélio/metabolismo , Morfogênese/fisiologia , Transdução de Sinais/fisiologia , Animais , Feminino , Humanos , Rim/embriologia , Rim/crescimento & desenvolvimento , Rim/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Glândulas Mamárias Humanas/metabolismo , Glândulas Salivares/embriologia , Glândulas Salivares/crescimento & desenvolvimento , Glândulas Salivares/metabolismoRESUMO
Epithelial cells contribute to the development of various vital organs by generating tubular and/or glandular architectures. The fully developed forms of ductal organs depend on processes of branching morphogenesis, whereby frequency, total number, and complexity of the branching tissue define the final architecture in the organ. Some ductal tissues, like the mammary gland during pregnancy and lactation, disintegrate and regenerate through periodic cycles. Differentiation of branched epithelia is driven by antagonistic actions of parallel growth factor systems that mediate epithelial-mesenchymal communication. Transforming growth factor-ß (TGF-ß) family members and their extracellular antagonists are prominently involved in both normal and disease-associated (e.g., malignant or fibrotic) ductal tissue patterning. Here, we discuss collective knowledge that permeates the roles of TGF-ß family members in the control of the ductal tissues in the vertebrate body.
Assuntos
Morfogênese , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Transição Epitelial-Mesenquimal , Feminino , Humanos , Pulmão/embriologia , Masculino , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Humanas/embriologia , Organogênese , Pâncreas/embriologia , Próstata/embriologia , Glândulas Salivares/embriologiaRESUMO
The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology, and spatial patterning, are encoded. Here, we show that, in mouse mammary gland, kidney, and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures develop as a self-organized process, reliant upon a strikingly simple but generic rule, without recourse to a rigid and deterministic sequence of genetically programmed events.
Assuntos
Rim/crescimento & desenvolvimento , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Modelos Biológicos , Morfogênese , Próstata/crescimento & desenvolvimento , Animais , Feminino , Humanos , Rim/embriologia , Masculino , Glândulas Mamárias Humanas/embriologia , Camundongos , Próstata/embriologiaRESUMO
Branched networks are ubiquitous throughout nature, particularly found in tissues that require large surface area within a restricted volume. Many tissues with a branched architecture, such as the vasculature, kidney, mammary gland, lung and nervous system, function to exchange fluids, gases and information throughout the body of an organism. The generation of branched tissues requires regulation of branch site specification, initiation and elongation. Branching events often require the coordination of many cells to build a tissue network for material exchange. Recent evidence has emerged suggesting that cell cooperativity scales with the number of cells actively contributing to branching events. Here, we compare mechanisms that regulate branching, focusing on how cell cohorts behave in a coordinated manner to build branched tissues.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.
Assuntos
Desenvolvimento Embrionário , Morfogênese , Animais , Sistema Cardiovascular/embriologia , Epitélio/embriologia , Epitélio/crescimento & desenvolvimento , Humanos , Rim/embriologia , Pulmão/embriologia , Glândulas Mamárias Humanas/embriologia , Sistema Nervoso/embriologiaAssuntos
Evolução Biológica , Epiderme/embriologia , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Humanas/embriologia , Leite/metabolismo , Modelos Teóricos , Animais , Feminino , Humanos , Lactação/fisiologia , Masculino , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Mamilos/embriologia , Diferenciação Sexual/fisiologiaRESUMO
The mammary gland undergoes dramatic post-natal growth beginning at puberty, followed by full development occurring during pregnancy and lactation. Following lactation, the alveoli undergo apoptosis, and the mammary gland reverses back to resemble the nonparous gland. This process of growth and regression occurs for multiple pregnancies, suggesting the presence of a hierarchy of stem and progenitor cells that are able to regenerate specialized populations of mammary epithelial cells. Expansion of epithelial cell populations in the mammary gland is regulated by ovarian steroids, in particular estrogen acting through its receptor estrogen receptor alpha (ERα) and progesterone signaling through progesterone receptor (PR). A diverse number of stem and progenitor cells have been identified based on expression of cell surface markers and functional assays. Here we review the current understanding of how estrogen and progesterone act together and separately to regulate stem and progenitor cells within the human and mouse mammary tissues. Better understanding of the hierarchal organization of epithelial cell populations in the mammary gland and how the hormonal milieu affects its regulation may provide important insights into the origins of different subtypes of breast cancer.
Assuntos
Epitélio/metabolismo , Estrogênios/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Gravidez/fisiologia , Progesterona/metabolismo , Células-Tronco/fisiologia , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Paridade/fisiologia , Receptores de Progesterona/metabolismo , Células-Tronco/metabolismo , Fatores de TranscriçãoRESUMO
The aim of this review is to focus on the molecular factors that ensure the optimal development and maintenance of the mammary gland thanks to their integration and coordination. The development of the mammary gland is supported, not only by endocrine signals, but also by regulatory molecules, which are able to integrate signals from the surrounding microenvironment. A major role is certainly played by homeotic genes, but their incorrect expression during the spatiotemporal regulation of proliferative, functional and differentiation cycles of the mammary gland, may result in the onset of neoplastic processes. Attention is directed also to the endocrine aspects and sexual dimorphism of mammary gland development, as well as the role played by ovarian steroids and their receptors in adult life.
Assuntos
Diferenciação Celular , Proliferação de Células , Glândulas Mamárias Humanas , Transdução de Sinais , Nicho de Células-Tronco , Adulto , Neoplasias da Mama/embriologia , Desenvolvimento Embrionário , Feminino , Humanos , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimentoRESUMO
Supernumerary nipples (or polythelia) usually appear along the embryonic milk lines or in other sites including the back, thigh, vulva, neck etc. The frequency of polythelia ranges from 0.2% to 5.6%. Despite the plethora of published cases concerning its association with other congenital malformations or syndromes with different patterns of inheritance, polythelia still remains a controversial and theoretical issue. Although most reports describe a link between supernumerary nipples and kidney/urinary tract anomalies, a potential relationship with other congenital anomalies or malignancies has also been speculated. Additionally, polythelia has been associated with genodermatoses, thus being related with an increased malignant potential, as well as with an increased risk for solid tumors such as renal adenocarcinoma, testicular cancer, prostate cancer, and urinary bladder carcinoma. The fact that the Scaramanga (ska) mutant mice presented with ectopic breast tissue imply that misregulation of the neuregulin-3 signaling pathway may be critical in the occurrence of polythelia. This is an attempt to review existing literature in order to (a) draw reliable conclusions whether polythelia is a manifestation of simple atavism or may be associated with concomitant severe conditions needing further investigation and/or management, (b) elucidate its aetiology and (c) establish appropriate clinical and laboratory approach.
Assuntos
Mamilos/anormalidades , Doenças Mamárias/diagnóstico , Doenças Mamárias/epidemiologia , Doenças Mamárias/genética , Anormalidades Congênitas , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Glândulas Mamárias Humanas/embriologia , Neoplasias , Puberdade , Fatores de Risco , Síndrome , Sistema Urinário/anormalidadesRESUMO
Extracellular matrix (ECM), a major component of the cellular microenvironment, plays critical roles in normal tissue morphogenesis and disease progression. Binding of ECM to membrane receptor proteins, such as integrin, discoidin domain receptors, and dystroglycan, elicits biochemical and biomechanical signals that control cellular architecture and gene expression. These ECM signals cooperate with growth factors and hormones to regulate cell migration, differentiation, and transformation. ECM signaling is tightly regulated during normal mammary gland development. Deposition and alignment of fibrillar collagens direct migration and invasion of mammary epithelial cells during branching morphogenesis. Basement membrane proteins are required for polarized acinar morphogenesis and milk protein expression. Deregulation of ECM proteins in the long run is sufficient to promote breast cancer development and progression. Recent studies demonstrate that the integrated biophysical and biochemical signals from ECM and soluble factors are crucial for normal mammary gland development as well as breast cancer progression.
Assuntos
Neoplasias da Mama/metabolismo , Matriz Extracelular/metabolismo , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/metabolismo , Neoplasias da Mama/patologia , Progressão da Doença , Matriz Extracelular/patologia , Feminino , Humanos , Transdução de Sinais/fisiologiaRESUMO
Many organs of higher organisms are heavily branched structures and arise by an apparently similar process of branching morphogenesis. Yet the regulatory components and local interactions that have been identified differ greatly in these organs. It is an open question whether the regulatory processes work according to a common principle and how far physical and geometrical constraints determine the branching process. Here, we review the known regulatory factors and physical constraints in lung, kidney, pancreas, prostate, mammary gland and salivary gland branching morphogenesis, and describe the models that have been formulated to analyse their impacts.
Assuntos
Rim/embriologia , Pulmão/embriologia , Glândulas Mamárias Humanas/embriologia , Pâncreas/embriologia , Próstata/embriologia , Glândulas Salivares/embriologia , Animais , Simulação por Computador , Humanos , Masculino , Modelos Biológicos , MorfogêneseRESUMO
The explant culture techniques of embryonic tissues allow continuous monitoring of organ growth and morphogenesis ex vivo. The effect of growth factors and other soluble molecules can be examined by applying them to the culture medium. Relatively few studies have reported application of tissue culture techniques to analysis of embryonic mammary glands. Here we describe a protocol for murine mammary rudiments that permits ex vivo development up to branching stage.
Assuntos
Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Técnicas de Cultura de Órgãos/métodos , Animais , Humanos , CamundongosRESUMO
We propose a new scenario for mammary evolution based on comparative review of early mammary development among mammals. Mammary development proceeds through homologous phases across taxa, but evolutionary modifications in early development produce different final morphologies. In monotremes, the mammary placode spreads out to form a plate-like mammary bulb from which more than 100 primary sprouts descend into mesenchyme. At their distal ends, secondary sprouts develop, including pilosebaceous anlagen, resulting in a mature structure in which mammary lobules and sebaceous glands empty into the infundibula of hair follicles; these structural triads (mammolobular-pilo-sebaceous units or MPSUs) represent an ancestral condition. In marsupials a flask-like mammary bulb elongates as a sprout, but then hollows out; its secondary sprouts include hair and sebaceous anlagen (MPSUs), but the hairs are shed during nipple formation. In some eutherians (cat, horse, human) MPSUs form at the distal ends of primary sprouts; pilosebaceous components either regress or develop into mature structures. We propose that a preexisting structural triad (the apocrine-pilo-sebaceous unit) was incorporated into the evolving mammary structure, and coupled to additional developmental processes that form the mammary line, placode, bulb and primary sprout. In this scenario only mammary ductal trees and secretory tissue derive from ancestral apocrine-like glands. The mammary gland appears to have coopted signaling pathways and genes for secretory products from even earlier integumentary structures, such as odontode (tooth-like) or odontode-derived structures. We speculate that modifications in signal use (such as PTHrP and BMP4) may contribute to taxonomic differences in MPSU development.
Assuntos
Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Humanas/embriologia , Animais , Evolução Biológica , Feminino , HumanosAssuntos
Neoplasias da Mama/patologia , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Humanas/embriologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Neoplasias Mamárias Experimentais/patologia , Animais , Feminino , HumanosRESUMO
Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in arrested mammary buds at day 15 of embryonic development (E15). In contrast, overexpression of PTHrP converts the ventral epidermis into hairless nipple skin. PTHrP signaling appears to be critical for mammary mesenchyme specification, which in turn maintains mammary epithelial identity, directs bud outgrowth, disrupts the male mammary rudiment and specifies the formation of the nipple. In the embryonic mammary bud, PTHrP exerts its effects on morphogenesis, in part, through epithelial-stromal crosstalk mediated by Wnt and BMP signaling. Recently, PTHLH has been identified as a strong candidate for a novel breast cancer susceptibility locus, although PTHrP's role in breast cancer has not been clearly defined. The effects of PTHrP on the growth of the embryonic mammary rudiment and its invasion into the dermis may, in turn, have connections to the role of PTHrP in breast cancer.
Assuntos
Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Humanas/embriologia , Mesoderma/embriologia , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Animais , Feminino , Humanos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Mesoderma/metabolismoRESUMO
Whole-mount immunofluorescent staining facilitates the profiling of protein expression patterns within diverse and complex tissues. Thanks to the application of antibodies on whole mounted instead of sectioned specimens, this technique has many advantages with respect to the preservation of biological and pathological features of specimens when compared to conventional immunohistological methods. Here, we describe a protocol and optimal conditions of whole-mount immunofluorescence for studying the formation of mammary primordia. We also show an example three-dimensional reconstruction of a mammary primordium based on z-stacked images of a whole-mount stained specimen using confocal microscopy and image analysis software.