Difference between revisions of "Talk:Integumentary System - Mammary Gland Development"
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Revision as of 17:19, 18 October 2017
Ror2 regulates branching, differentiation, and actin-cytoskeletal dynamics within the mammary epithelium
J Cell Biol. 2015 Feb 2;208(3):351-66. doi: 10.1083/jcb.201408058. Epub 2015 Jan 26.
Roarty K1, Shore AN1, Creighton CJ1, Rosen JM2.
Wnt signaling encompasses β-catenin-dependent and -independent networks. How receptor context provides Wnt specificity in vivo to assimilate multiple concurrent Wnt inputs throughout development remains unclear. Here, we identified a refined expression pattern of Wnt/receptor combinations associated with the Wnt/β-catenin-independent pathway in mammary epithelial subpopulations. Moreover, we elucidated the function of the alternative Wnt receptor Ror2 in mammary development and provided evidence for coordination of this pathway with Wnt/β-catenin-dependent signaling in the mammary epithelium. Lentiviral short hairpin RNA (shRNA)-mediated depletion of Ror2 in vivo increased branching and altered the differentiation of the mammary epithelium. Microarray analyses identified distinct gene level alterations within the epithelial compartments in the absence of Ror2, with marked changes observed in genes associated with the actin cytoskeleton. Modeling of branching morphogenesis in vitro defined specific defects in cytoskeletal dynamics accompanied by Rho pathway alterations downstream of Ror2 loss. The current study presents a model of Wnt signaling coordination in vivo and assigns an important role for Ror2 in mammary development. © 2015 Roarty et al. PMID 25624393
Gli activity is critical at multiple stages of embryonic mammary and nipple development
PLoS One. 2013 Nov 18;8(11):e79845. doi: 10.1371/journal.pone.0079845. eCollection 2013.
Chandramouli A1, Hatsell SJ, Pinderhughes A, Koetz L, Cowin P.
Gli3 is a transcriptional regulator of Hedgehog (Hh) signaling that functions as a repressor (Gli3(R)) or activator (Gli3(A)) depending upon cellular context. Previously, we have shown that Gli3(R) is required for the formation of mammary placodes #3 and #5. Here, we report that this early loss of Gli3 results in abnormal patterning of two critical regulators: Bmp4 and Tbx3, within the presumptive mammary rudiment (MR) #3 zone. We also show that Gli3 loss leads to failure to maintain mammary mesenchyme specification and loss of epithelial Wnt signaling, which impairs the later development of remaining MRs: MR#2 showed profound evagination and ectopic hairs formed within the presumptive areola; MR#4 showed mild invagination defects and males showed inappropriate retention of mammary buds in Gli3(xt/xt) mice. Importantly, mice genetically manipulated to misactivate Hh signaling displayed the same phenotypic spectrum demonstrating that the repressor function of Gli3(R) is essential during multiple stages of mammary development. In contrast, positive Hh signaling occurs during nipple development in a mesenchymal cuff around the lactiferous duct and in muscle cells of the nipple sphincter. Collectively, these data show that repression of Hh signaling by Gli3(R) is critical for early placodal patterning and later mammary mesenchyme specification whereas positive Hh signaling occurs during nipple development.
Evolution of immune functions of the mammary gland and protection of the infant
Breastfeed Med. 2012 Jun;7(3):132-42. doi: 10.1089/bfm.2012.0025. Epub 2012 May 11.
Goldman AS. Author information
Abstract The evolution of immunological agents in milk is intertwined with the general aspects of the evolution of the mammary gland. In that respect, mammalian precursors emerged from basal amniotes some 300 million years ago. In contrast to the predominant dinosaurs, proto-mammals possessed a glandular skin. A secondary palate in the roof of the mouth that directed airflow from the nostrils to the oropharynx and thus allowed mammals to ingest and breathe simultaneously first appeared in cynodonts 230 million years ago. This set the stage for mammalian newborns to nurse from the future mammary gland. Interplays between environmental and genetic changes shaped mammalian evolution including the mammary gland from dermal glands some 160 millions of years ago. It is likely that secretions from early mammary glands provided nutrients and immunological agents for the infant. Natural selection culminated in milks uniquely suited to nourish and protect infants of each species. In human milk, antimicrobial, anti-inflammatory, and immunoregulatory agents and living leukocytes are qualitatively or quantitatively different from those in other mammalian milks. Those in human milk compensate for developmental delays in the immunological system of the recipient infant. Consequently, the immune system in human milk provided by evolution is much of the basis for encouraging breastfeeding for human infants. Comment in The evolution of the mammary gland and the milk it produces. [Breastfeed Med. 2012] PMID 22577734
Akt1 is essential for postnatal mammary gland development, function, and the expression of Btn1a1
PLoS One. 2011;6(9):e24432. Epub 2011 Sep 7.
LaRocca J, Pietruska J, Hixon M. Source Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America. email@example.com
Akt1, a serine-threonine protein kinase member of the PKB/Akt gene family, plays critical roles in the regulation of multiple cellular processes, and has previously been implicated in lactation and breast cancer development. In this study, we utilized Akt1+/+ and Akt1-/- C57/Bl6 female mice to assess the role that Akt1 plays in normal mammary gland postnatal development and function. We examined postnatal morphology at multiple time points, and analyzed gene and protein expression changes that persist into adulthood. Akt1 deficiency resulted in several mammary gland developmental defects, including ductal outgrowth and defective terminal end bud formation. Adult Akt1-/- mammary gland composition remained altered, exhibiting fewer alveolar buds coupled with increased epithelial cell apoptosis. Microarray analysis revealed that Akt1 deficiency altered expression of genes involved in numerous biological processes in the mammary gland, including organismal development, cell death, and tissue morphology. Of particular importance, a significant decrease in expression of Btn1a1, a gene involved in milk lipid secretion, was observed in Akt1-/- mammary glands. Additionally, pseudopregnant Akt1-/- females failed to induce Btn1a1 expression in response to hormonal stimulation compared to their wild-type counterparts. Retroviral-mediated shRNA knockdown of Akt1 and Btn1a1 in MCF-7 human breast epithelial further illustrated the importance of Akt1 in mammary epithelial cell proliferation, as well as in the regulation of Btn1a1 and subsequent expression of ß-casein, a gene that encodes for milk protein. Overall these findings provide mechanistic insight into the role of Akt1 in mammary morphogenesis and function.
Redefining the expression and function of the inhibitor of differentiation 1 in mammary gland development
PLoS One. 2010 Aug 3;5(8):e11947.
Nair R, Junankar S, O'Toole S, Shah J, Borowsky AD, Bishop JM, Swarbrick A.
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. Abstract The accumulation of poorly differentiated cells is a hallmark of breast neoplasia and progression. Thus an understanding of the factors controlling mammary differentiation is critical to a proper understanding of breast tumourigenesis. The Inhibitor of Differentiation 1 (Id1) protein has well documented roles in the control of mammary epithelial differentiation and proliferation in vitro and breast cancer progression in vivo. However, it has not been determined whether Id1 expression is sufficient for the inhibition of mammary epithelial differentiation or the promotion of neoplastic transformation in vivo. We now show that Id1 is not commonly expressed by the luminal mammary epithelia, as previously reported. Generation and analysis of a transgenic mouse model of Id1 overexpression in the mammary gland reveals that Id1 is insufficient for neoplastic progression in virgin animals or to prevent terminal differentiation of the luminal epithelia during pregnancy and lactation. Together, these data demonstrate that there is no luminal cell-autonomous role for Id1 in mammary epithelial cell fate determination, ductal morphogenesis and terminal differentiation.
Molecular mechanisms guiding embryonic mammary gland development
Cold Spring Harb Perspect Biol. 2010 Jun 1;2(6):a003251. Epub 2010 May 19.
Cowin P, Wysolmerski J.
Departments of Cell Biology and Dermatology, New York University School of Medicine, New York, NY 10016, USA. Abstract The mammary gland is an epidermal appendage that begins to form during embryogenesis, but whose development is only completed during pregnancy. Each mammary gland begins as a budlike invagination of the surface ectoderm, which then gives rise to a simple duct system by birth. Subsequent development occurs during sexual maturation and during pregnancy and lactation. In this review, we outline the distinct stages of embryonic mammary development and discuss the molecular pathways involved in the regulation of morphogenesis at each stage. We also discuss the potential relevance of embryonic breast development to the pathophysiology of breast cancer and highlight questions for future research.
Editorial: The mammary stroma in normal development and function
J Mammary Gland Biol Neoplasia. 2010 Sep;15(3):275-7. Epub 2010 Sep 9.
Schedin P, Hovey RC.
Abstract The mammary gland can no longer be simply viewed as an organ composed of epithelial cells within a passive stromal microenvironment. Many lines of evidence have evolved to reinforce the notion that mammary epithelial cell growth, differentiation, lactation and progression to cancer involves bidirectional interactions between the epithelial population and its surrounding stroma. Within this stroma are numerous systems that are all capable of modulating epithelial function. In this context, the mammary stroma is not simply a depot of adipose tissue in which mammary epithelial cells undertake a unique growth and differentiation process, although adipocytes can impart numerous modulatory signals to epithelial cells, and vice versa. Rather, the stromal environment constitutes and supports a critical vasculature that supplies nutrients and endocrine cues, a lymphatic system that not only removes metabolites but also provides an intimate interface with the immune system, and an extracellular matrix scaffold in which epithelial cells grow, differentiate and regress. Ultimately all of these components play a critical role in directing the epithelial phenotype during normal mammary gland growth and function. An increasing appreciation for these different systems demands a view of mammary epithelial cells in a much different light, and further necessitates the development of model systems that incorporate and integrate increasing complexity.
Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation
Jiang P, Hu Q, Ito M, Meyer S, Waltz S, Khan S, Roeder RG, Zhang X. Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6765-70. Epub 2010 Mar 29.
Mediator recently has emerged as a central player in the direct transduction of signals from transcription factors to the general transcriptional machinery. In the case of nuclear receptors, in vitro studies have shown that the transcriptional coactivator function of the Mediator involves direct ligand-dependent interactions of the MED1 subunit, through its two classical LxxLL motifs, with the receptor AF2 domain. However, despite the strong in vitro evidence, there currently is little information regarding in vivo functions of the LxxLL motifs either in MED1 or in other coactivators. Toward this end, we have generated MED1 LxxLL motif-mutant knockin mice. Interestingly, these mice are both viable and fertile and do not exhibit any apparent gross abnormalities. However, they do exhibit severe defects in pubertal mammary gland development. Consistent with this phenotype, as well as loss of the strong ligand-dependent estrogen receptor (ER)alpha-Mediator interaction, expression of a number of known ERalpha-regulated genes was down-regulated in MED1-mutant mammary epithelial cells and could no longer respond to estrogen stimulation. Related, estrogen-stimulated mammary duct growth in MED1-mutant mice was also greatly diminished. Finally, additional studies show that MED1 is differentially expressed in different types of mammary epithelial cells and that its LxxLL motifs play a role in mammary luminal epithelial cell differentiation and progenitor/stem cell determination. Our results establish a key nuclear receptor- and cell-specific in vivo role for MED1 LxxLL motifs, through Mediator-ERalpha interactions, in mammary gland development.
Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways
Lim E, Wu D, Pal B, Bouras T, Asselin-Labat ML, Vaillant F, Yagita H, Lindeman GJ, Smyth GK, Visvader JE. Breast Cancer Res. 2010;12(2):R21. Epub 2010 Mar 26.
INTRODUCTION: Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step toward understanding pathways that regulate self-renewal, lineage commitment, and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis and to compare with their normal human counterpart subsets to identify conserved genes and networks.
METHODS: RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.
RESULTS: The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, whereas the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, whereas IPA highlighted a number of conserved pathways in the three epithelial subsets.
CONCLUSIONS: The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in the different models.
The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation
Development. 2010 Mar;137(6):945-52. Epub 2010 Feb 11.
Wellberg E, Metz RP, Parker C, Porter WW.
Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4458, USA. Abstract We have previously demonstrated that the bHLH/PAS transcription factor, singleminded 2s (Sim2s), is required for proper mammary ductal morphogenesis and luminal epithelial differentiation. Furthermore, loss of Sim2s in breast cancer cells resulted in downregulation of epithelial markers and acquisition of a basal-like phenotype. The objective of this study was to further define the role of Sim2s in mammary differentiation. We found that Sim2s is developmentally regulated throughout mammary gland development with highest expression during lactation. Mammary glands from nulliparous mice expressing Sim2s driven by the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) promoter were morphologically indistinguishable from wild-type mice but displayed hallmarks of precocious lactogenic differentiation. These included elevated expression of the milk protein genes Wap and Csn2, and apical localization of the lactation marker Npt2b. Consistent with the in vivo results, Sim2s enhanced prolactin-mediated Csn2 expression in HC11 and CIT3 mouse mammary epithelial cells, and downregulation of Sim2s by shRNA in HC11 cells inhibited Csn2 expression. Chromatin immunoprecipitation (ChIP) analyses of the Csn2 gene found that Sim2s associates with the Csn2 promoter and re-ChIP experiments showed that Sim2s interacted with the RNA II polymerase (RNAPII) complex. Together, these data demonstrate, for the first time, that Sim2s is required for establishing and maintaining mammary gland differentiation.
Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2989-94. Epub 2010 Jan 28.
Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y, Schneider P, Brisken C.
Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research (ISREC), NCCR Molecular Oncology, CH-1015 Lausanne, Switzerland. Abstract The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor alpha (ERalpha) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(-) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-kappaB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR(-/-) phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.
A novel mouse model for non-invasive single marker tracking of mammary stem cells in vivo reveals stem cell dynamics throughout pregnancy
Tiede BJ, Owens LA, Li F, DeCoste C, Kang Y. PLoS One. 2009 Nov 25;4(11):e8035.
Mammary stem cells (MaSCs) play essential roles for the development of the mammary gland and its remodeling during pregnancy. However, the precise localization of MaSCs in the mammary gland and their regulation during pregnancy is unknown. Here we report a transgenic mouse model for luciferase-based single marker detection of MaSCs in vivo that we used to address these issues. Single transgene expressing mammary epithelial cells were shown to reconstitute mammary glands in vivo while immunohistochemical staining identified MaSCs in basal and luminal locations, with preponderance towards the basal position. By quantifying luciferase expression using bioluminescent imaging, we were able to track MaSCs non-invasively in individual mice over time. Using this model to monitor MaSC dynamics throughout pregnancy, we found that MaSCs expand in both total number and percentage during pregnancy and then drop down to or below baseline levels after weaning. However, in a second round of pregnancy, this expansion was not as extensive. These findings validate a powerful system for the analysis of MaSC dynamics in vivo, which will facilitate future characterization of MaSCs during mammary gland development and breast cancer.
Anatomy of the lactating human breast redefined with ultrasound imaging
J Anat. 2005 Jun;206(6):525-34.
Ramsay DT1, Kent JC, Hartmann RA, Hartmann PE.
The aim of this study was to use ultrasound imaging to re-investigate the anatomy of the lactating breast. The breasts of 21 fully lactating women (1-6 months post partum) were scanned using an ACUSON XP10 (5-10 MHz linear array probe). The number of main ducts was measured, ductal morphology was determined, and the distribution of glandular and adipose tissue was recorded. Milk ducts appeared as hypoechoic tubular structures with echogenic walls that often contained echoes. Ducts were easily compressed and did not display typical sinuses. All ducts branched within the areolar radius, the first branch occurring 8.0 +/- 5.5 mm from the nipple. Duct diameter was 1.9 +/- 0.6 mm, 2.0 +/- 90.7 mm and the number of main ducts was 9.6 +/- 2.9, 9.2 +/- 2.9, for left and right breast, respectively. Milk ducts are superficial, easily compressible and echoes within the duct represent fat globules in breastmilk. The low number and size of the ducts, the rapid branching under the areola and the absence of sinuses suggest that ducts transport breastmilk, rather than store it. The distribution of adipose and glandular tissue showed wide variation between women but not between breasts within women. The proportion of glandular and fat tissue and the number and size of ducts were not related to milk production. This study highlights inconsistencies in anatomical literature that impact on breast physiology, breastfeeding management and ultrasound assessment.
Supernumerary nipples: prevalence, size, sex and side predilection -- a prospective clinical study
Eur J Pediatr. 1998 Oct;157(10):821-3.
The purpose of the following clinical study was to determine the prevalence, size, sex and side predilection of supernumerary nipples. Out of 502 patients, 28 (5.6%) exhibited a supernumerary nipple of small (only areola with diameter less than 30% of normal areola) or middle size (areola with nipple, diameter 30%-50% of normal areola). The male/female ratio was 20/8 and left/right side ratio 15/7 in males and 5/4 in females. CONCLUSION: A supernumerary areola or a supernumerary areola with nipple is a frequent finding. There is a higher prevalence for the left side and male gender. PMID: 9809822