Gli3-mediated repression of Hedgehog targets is required for normal mammary development

Hatsell, Sarah; Cowin, Pamela

doi:10.1242/dev.02542

Cited by 99 publications

(141 citation statements)

References 77 publications

(76 reference statements)

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…The development of the APSU occurs in coordinated fashion, no doubt because of crosstalk between the differentiating epithelial cells and underlying mesenchyme, as well as differences in signaling pathways and receptors of the hair follicle, apocrine gland, and sebaceous gland (Hatsell and Cowin, 2006;Andrechek et al, 2008;Mayer et al, 2008). The apocrine gland duct typically opens into the infundibulum of the hair follicle, such that secretion contacts the hair shaft.…”

Section: The Evolution Of Mammary Secretionmentioning

confidence: 99%

The evolution of milk secretion and its ancient origins

Oftedal

2012

Animal

187

142

View full text Add to dashboard Cite

Lactation represents an important element of the life history strategies of all mammals, whether monotreme, marsupial, or eutherian. Milk originated as a glandular skin secretion in synapsids (the lineage ancestral to mammals), perhaps as early as the Pennsylvanian period, that is, approximately 310 million years ago (mya). Early synapsids laid eggs with parchment-like shells intolerant of desiccation and apparently dependent on glandular skin secretions for moisture. Mammary glands probably evolved from apocrine-like glands that combined multiple modes of secretion and developed in association with hair follicles. Comparative analyses of the evolutionary origin of milk constituents support a scenario in which these secretions evolved into a nutrient-rich milk long before mammals arose. A variety of antimicrobial and secretory constituents were co-opted into novel roles related to nutrition of the young. Secretory calcium-binding phosphoproteins may originally have had a role in calcium delivery to eggs; however, by evolving into large, complex casein micelles, they took on an important role in transport of amino acids, calcium and phosphorus. Several proteins involved in immunity, including an ancestral butyrophilin and xanthine oxidoreductase, were incorporated into a novel membrane-bound lipid droplet (the milk fat globule) that became a primary mode of energy transfer. An ancestral c-lysozyme lost its lytic functions in favor of a role as a-lactalbumin, which modifies a galactosyltransferase to recognize glucose as an acceptor, leading to the synthesis of novel milk sugars, of which free oligosaccharides may have predated free lactose. An ancestral lipocalin and an ancestral whey acidic protein four-disulphide core protein apparently lost their original transport and antimicrobial functions when they became the whey proteins b-lactoglobulin and whey acidic protein, which with a-lactalbumin provide limiting sulfur amino acids to the young. By the late Triassic period (ca 210 mya), mammaliaforms (mammalian ancestors) were endothermic (requiring fluid to replace incubatory water losses of eggs), very small in size (making large eggs impossible), and had rapid growth and limited tooth replacement (indicating delayed onset of feeding and reliance on milk). Thus, milk had already supplanted egg yolk as the primary nutrient source, and by the Jurassic period (ca 170 mya) vitellogenin genes were being lost. All primary milk constituents evolved before the appearance of mammals, and some constituents may have origins that predate the split of the synapsids from sauropsids (the lineage leading to 'reptiles' and birds). Thus, the modern dairy industry is built upon a very old foundation, the cornerstones of which were laid even before dinosaurs ruled the earth in the Jurassic and Cretaceous periods.Keywords: evolution, lactation, milk composition, casein, milk fat globule ImplicationsLactation has an evolutionary origin and biological context within which its secretory processes and milk constituents evolved. This revi...

show abstract

Section: The Evolution Of Mammary Secretionmentioning

confidence: 99%

The evolution of milk secretion and its ancient origins

Oftedal

2012

Animal

187

142

View full text Add to dashboard Cite

show abstract

“…Recent work from Sarah Hatsell has demonstrated the importance of repressing Hedgehog signaling for the normal development of the embryonic mammary gland whereas Andra Frost has shown that Hedgehog activation occurs in breast carcinoma [21,22]. This article reviews recent data that show that failure to repress Hedgehog activation in carcinoma cells and stromal misactivation of Hedgehog signaling critically influence tumor progression in both human and mouse models of cancer.…”

mentioning

confidence: 91%

Breast Cancer Progression: Controversies and Consensus in the Molecular Mechanisms of Metastasis and EMT

Cowin

Welch

2007

J Mammary Gland Biol Neoplasia

Self Cite

View full text Add to dashboard Cite

Breast cancer is the second most frequent form of female cancer and a major source of cancer death worldwide. Although breast cancer has long been part of the human condition, appearing in the writings of ancient Egyptians, modern breast cancer shows a disturbing statistical increase from 1 per 20 women in the 1960s to one in eight today [1]. Although early detection by mammography and adjuvant therapies has improved survival, the absence of good prognostic criteria continues to result in overtreatment of patients with benign disease and failure to identify and eliminate the source of metastatic breast cancer.This issue is concerned with the myriad stages of tumor progression that lead to the dissemination of breast cancer cells from the primary tumor and propagation at distant sites. The first stage in this progression involves loss of local constraints, both physical and regulatory, emanating from neighboring normal cells and surrounding stroma. The second step termed intravasation, involves entering a circulatory system (blood and/or lymphatic), the third dissemination and survival within hostile ectopic environments, and the fourth organotropic colonization of compatible sites.Considerable debate has arisen between elements in the scientific and clinical community concerning the proposed mechanisms of metastatic spread [2,3]. The controversy centers on whether metastasis involves inappropriate transient re-enactment of developmental migratory processes; Darwinian selection within a population of genomically unstable, rapidly evolving cancer cells for attributes that facilitate growth in and exploitation of new environs; or a combination of both.Seeing parallels between the metastatic process and the long-distance migration of cells during development, cell and developmental biologists have invoked epithelial-mesenchymal transition (EMT) as the mechanistic basis for breast cancer metastasis [4][5][6]. In its strictest sense, EMT and its converse MET, have been used to describe conversions in cell shape and migratory behavior that accompany cell fate changes during embryonic development. A classical example of EMT is the emergence from the coherent neural plate of migratory neural crest cells, which travel long distances and adopt many different mesenchymal cell fates. These events involve the loss of "epithelial" characteristics such as cell-cell adhesion mechanisms and junctions and switching on of vimentin expression as the major intermediate filament protein. Further analyses have revealed the essential role of a genetic program tightly

show abstract

“…In analogy mammary gland development is dependent on epithelial-mesenchymal interactions and the Hh pathway is emerging as one important factor during mammary gland development (13)(14)(15)(16)(17). Development of the mouse mammary gland is initiated around day 10.5 of embryonic development with the formation of bilateral milk lines running between the fore and hind limbs.…”

mentioning

confidence: 99%

“…However, it is interesting to note that Ihh expression is regulated by progesterone, one of the key steroid hormones controlling ductal and alveolar development in the mammary gland (23)(24)(25). The core components (Shh, Ihh, Dhh, Ptch1, Smo, Gli1, Gli2, Gli3) of the Hh signaling pathway have been reported to be expressed during essentially all stages of mammary gland development (13,15,19). Expression of Hh pathway components varies during the different phases of mammary gland development and is progressively elevated during pregnancy and a peak of expression is detected during lactation (13,14,19).…”

mentioning

confidence: 99%

“…The core components (Shh, Ihh, Dhh, Ptch1, Smo, Gli1, Gli2, Gli3) of the Hh signaling pathway have been reported to be expressed during essentially all stages of mammary gland development (13,15,19). Expression of Hh pathway components varies during the different phases of mammary gland development and is progressively elevated during pregnancy and a peak of expression is detected during lactation (13,14,19). Furthermore, the Hedgehog signaling components PTCH1, GLI1, and GLI2 are expressed in normal human mammary progenitor cells (26).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Targeted Expression of GLI1 in the Mammary Gland Disrupts Pregnancy-induced Maturation and Causes Lactation Failure

Fiaschi

Rozell

Bergström

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The Hedgehog signaling pathway regulates the development and function of numerous tissues and when mis-regulated causes tumorigenesis. To assess the role of a deregulated Hedgehog signaling pathway in the mammary gland we targeted the expression of the Hedgehog effector protein, GLI1, to mammary epithelial cells using a bigenic inducible system. A constitutively active Hedgehog signaling pathway resulted with 100% penetrance in an undifferentiated mammary lobuloalveolar network during pregnancy. GLI1-expressing transgenic females were unable to lactate and milk protein gene expression was essentially absent. The inability to lactate was permanent and independent of continued GLI1 transgene expression. An increased expression of the GLI1 response gene Snail coupled to reduced expression of E-cadherin and STAT5 in the transgenic mammary gland provides a likely molecular explanation, underlying the observed phenotypic changes. In addition, remodeling of the mammary gland after parturition was impaired and expression of GLI1 was associated with accumulation of cellular debris in the mammary ducts during involution, indicating a defect in the clearance of dead cells. Areas with highly proliferative epithelial cells were observed in mammary glands with induced expression of GLI1. Within such areas an increased frequency of cells expressing nuclear Cyclin D1 was observed. Taken together the data support the notion that correct regulation of Hedgehog signaling within the epithelial cell compartment is critical for pregnancy-induced mammary gland development and remodeling.The Hedgehog (Hh) 2 signal transduction pathway controls a variety of developmental processes such as pattern formation, differentiation, proliferation, and organogenesis and when misregulated causes the formation of developmental defects and tumorigenesis. The molecular details of the Hh signaling pathway have been thoroughly investigated using genetic studies in Drosophila melanogaster (for review see Refs. 1 and 2). The hh signaling cascade starts by binding of hh to the receptor protein ptc, which abrogates its inhibitory effect on smoothened (smo), a 7-span transmembrane co-receptor protein. The active smo protein signals downstream to a microtubule-associated multiprotein complex resulting in a switch from generation of the proteolytically cleaved repressor form of the transcription factor ci to release of a full-length activator form of ci that enters the nucleus and activates target genes.The Hh signaling pathway is well conserved through evolution. However, it is far more complicated in vertebrates with three Hh genes, Sonic, Indian, and Desert (Shh, Ihh, and Dhh); two ptc genes (Ptch1 and Ptch2); and three ci homologues (Gli1, Gli2, and Gli3). In vertebrates, the Hh signal activates Gli2 initiating transcription of Hh target genes, including Ptch1 and Gli1 (3). Gli2 and Gli3 can be expressed in the absence of Hh signaling, whereas Gli1 is strictly dependent on Hh signaling for its expression, which makes Gli1 an excellent reporter of active H...

show abstract

Gli3-mediated repression of Hedgehog targets is required for normal mammary development

Cited by 99 publications

References 77 publications

The evolution of milk secretion and its ancient origins

The evolution of milk secretion and its ancient origins

Breast Cancer Progression: Controversies and Consensus in the Molecular Mechanisms of Metastasis and EMT

Targeted Expression of GLI1 in the Mammary Gland Disrupts Pregnancy-induced Maturation and Causes Lactation Failure

Contact Info

Product

Resources

About