Conditional Knockout of Lgr4 Leads to Impaired Ductal Elongation and Branching Morphogenesis in Mouse Mammary Glands

2011 ◽  
Vol 5 (4) ◽  
pp. 205-212 ◽  
Author(s):  
K. Oyama ◽  
Y. Mohri ◽  
M. Sone ◽  
A. Nawa ◽  
K. Nishimori
Keyword(s):  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Conditional Knockout ◽  
Ductal Elongation

The laminin-binding integrins regulate nuclear factor kappa-β-dependent epithelial cell polarity and inflammation

2021 ◽  
Author(s):  
Eugenia M. Yazlovitskaya ◽  
Erin Plosa ◽  
Fabian Bock ◽  
Olga M. Viquez ◽  
Glenda Mernaugh ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Polarity ◽  
Collecting Duct ◽  
Branching Morphogenesis ◽  
Conditional Knockout ◽  
Double Knockout ◽  
Epithelial Cell Polarity ◽  
Developing Kidney ◽  
Α3 Integrin ◽  
Collecting System

The main laminin (LM)-binding integrins α3β1, α6β1 and α6β4 are co-expressed in the developing kidney collecting duct (CD) system. We previously showed that deleting the integrin α3 or α6 subunit in the ureteric bud (UB), which gives rise to the kidney collecting system, caused either a mild or no branching morphogenesis phenotype, respectively. To determine whether these two integrin subunits co-operate in kidney CD development, we deleted α3 and α6 in the developing UB. The collecting system of the double knockout phenocopied the α3 integrin conditional knockout. However, with age the mice developed severe inflammation and fibrosis around the CDs resulting in kidney failure. Integrin α3α6 null CD epithelial cells showed increased secretion of pro-inflammatory cytokines and displayed mesenchymal characterisitcs causing loss of barrier function. These features resulted from increased NF-κB activity, which regulated the Snail/Slug transcription factors and their downstream targets. These data suggest that LM-binding integrins play a key role in the maintenance of kidney tubule epithelial cell polarity and decrease pro-inflammatory cytokine secretion by regulating NF-κB-dependent signaling.

scholarly journals Repressor of Estrogen Receptor Activity (REA) Is Essential for Mammary Gland Morphogenesis and Functional Activities: Studies in Conditional Knockout Mice

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4336-4349 ◽  
Author(s):  
Sunghee Park ◽  
Yuechao Zhao ◽  
Sangyeon Yoon ◽  
Jianming Xu ◽  
Lan Liao ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
Gene Dosage ◽  
Conditional Knockout ◽  
Loss Of Function ◽  
Breast Tumorigenesis ◽  
Pregnancy And Lactation ◽  
Ductal Elongation ◽  
Gland Development

Estrogen receptor (ER) is a key regulator of mammary gland development and is also implicated in breast tumorigenesis. Because ER-mediated activities depend critically on coregulator partner proteins, we have investigated the consequences of reduction or loss of function of the coregulator repressor of ER activity (REA) by conditionally deleting one allele or both alleles of the REA gene at different stages of mammary gland development. Notably, we find that heterozygosity and nullizygosity for REA result in very different mammary phenotypes and that REA has essential roles in the distinct morphogenesis and functions of the mammary gland at different stages of development, pregnancy, and lactation. During puberty, mice homozygous null for REA in the mammary gland (REAf/f PRcre/+) showed severely impaired mammary ductal elongation and morphogenesis, whereas mice heterozygous for REA (REAf/+ PRcre/+) displayed accelerated mammary ductal elongation, increased numbers of terminal end buds, and up-regulation of amphiregulin, the major paracrine mediator of estrogen-induced ductal morphogenesis. During pregnancy and lactation, mice with homozygous REA gene deletion in mammary epithelium (REAf/f whey acidic protein-Cre) showed a loss of lobuloalveolar structures and increased apoptosis of mammary alveolar epithelium, leading to impaired milk production and significant reduction in growth of their offspring, whereas body weights of the offspring nursed by females heterozygous for REA were slightly greater than those of control mice. Our findings reveal that REA is essential for mammary gland development and has a gene dosage-dependent role in the regulation of stage-specific physiological functions of the mammary gland.

scholarly journals Overexpression of a Kinase-deficient Transforming Growth Factor-β Type II Receptor in Mouse Mammary Stroma Results in Increased Epithelial Branching

1999 ◽  
Vol 10 (4) ◽  
pp. 1221-1234 ◽  
Author(s):  
Heather Joseph ◽  
Agnieszka E. Gorska ◽  
Philip Sohn ◽  
Harold L. Moses ◽  
Rosa Serra
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Dominant Negative ◽  
Type Ii ◽  
Ductal Epithelium ◽  
Lateral Branching

Members of the transforming growth factor-β (TGF-β) superfamily signal through heteromeric type I and type II serine/threonine kinase receptors. Transgenic mice that overexpress a dominant-negative mutation of the TGF-β type II receptor (DNIIR) under the control of a metallothionein-derived promoter (MT-DNIIR) were used to determine the role of endogenous TGF-βs in the developing mammary gland. The expression of the dominant-negative receptor was induced with zinc and was primarily localized to the stroma underlying the ductal epithelium in the mammary glands of virgin transgenic mice from two separate mouse lines. In MT-DNIIR virgin females treated with zinc, there was an increase in lateral branching of the ductal epithelium. We tested the hypothesis that expression of the dominant-negative receptor may alter expression of genes that are expressed in the stroma and regulated by TGF-βs, potentially resulting in the increased lateral branching seen in the MT-DNIIR mammary glands. The expression of hepatocyte growth factor mRNA was increased in mammary glands from transgenic animals relative to the wild-type controls, suggesting that this factor may play a role in TGF-β-mediated regulation of lateral branching. Loss of responsiveness to TGF-βs in the mammary stroma resulted in increased branching in mammary epithelium, suggesting that TGF-βs play an important role in the stromal–epithelial interactions required for branching morphogenesis.

scholarly journals Enhanced Branching Morphogenesis in Mammary Glands of Mice Lacking Cell Surface β1,4-Galactosyltransferase

2002 ◽  
Vol 244 (1) ◽  
pp. 114-133 ◽  
Author(s):  
Kristin Steffgen ◽  
Kimberly Dufraux ◽  
Helen Hathaway
Keyword(s):  
Cell Surface ◽  
Branching Morphogenesis ◽  
Mammary Glands

scholarly journals Chemokine receptors ACKR2 and CCR1 coordinate macrophage dynamics and mammary gland development

2019 ◽  
Author(s):  
Gillian J Wilson ◽  
Ayumi Fukuoka ◽  
Samantha R Love ◽  
Jiwon Kim ◽  
Marieke Pingen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Mammary Gland Development ◽  
Branching Morphogenesis ◽  
Unknown Mechanism ◽  
Key Population ◽  
Ductal Elongation ◽  
Gland Development

AbstractMacrophages are key regulators of developmental processes, including those involved in mammary gland development. We previously demonstrated that the atypical chemokine receptor, ACKR2, contributes to control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a chemokine-scavenging receptor, which mediates its effects through collaboration with inflammatory chemokine receptors (iCCRs). Here we reveal that ACKR2, and the iCCR CCR1, reciprocally regulate branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition estrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets.SummaryIn the mammary gland during puberty, availability of the chemokine CCL7 is controlled by a scavenging receptor ACKR2 and provides a key signal to macrophages which have the receptor CCR1. Together, this controls the timing of development.

scholarly journals Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo

Development ◽  
2002 ◽  
Vol 129 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Arnaud André Mailleux ◽  
Bradley Spencer-Dene ◽  
Christian Dillon ◽  
Delphine Ndiaye ◽  
Catherine Savona-Baron ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mammary Gland Development ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Fat Pad ◽  
Mammary Fat Pad ◽  
Gland Development ◽  
Mammary Placode ◽  
Dependent Pathway

The mouse develops five pairs of mammary glands that arise during mid-gestation from five pairs of placodes of ectodermal origin. We have investigated the molecular mechanisms of mammary placode development using Lef1 as a marker for the epithelial component of the placode, and mice deficient for Fgf10 or Fgfr2b, both of which fail to develop normal mammary glands. Mammary placode induction involves two different signaling pathways, a FGF10/FGFR2b-dependent pathway for placodes 1, 2, 3 and 5 and a FGF10/FGFR2b-independent pathway for placode 4. Our results also suggest that FGF signaling is involved in the maintenance of mammary bud 4, and that Fgf10 deficient epithelium can undergo branching morphogenesis into the mammary fat pad precursor.

scholarly journals A functional genetic screen identifies Aurora kinase b as a critical regulator of Sox9-positive embryonic lung progenitor cells

Development ◽  
2021 ◽  
Author(s):  
Ah-Cann C ◽  
Wimmer VC ◽  
Weeden CE ◽  
Marceaux C ◽  
Law CW ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Ex Vivo ◽  
Aurora Kinase ◽  
Postnatal Growth ◽  
Branching Morphogenesis ◽  
Genetic Screen ◽  
Conditional Knockout ◽  
Embryonic Lung ◽  
Aurora Kinase B

Development of a branching tree in the embryonic lung is critical for the formation of a fully mature functional lung at birth. Sox9+ cells present at the tip of the primary embryonic lung endoderm are multipotent cells responsible for branch formation and elongation. We performed a genetic screen and identified Aurora kinase b (Aurkb) as a critical regulator of Sox9+ cells ex vivo. In vivo conditional knockout studies confirmed that Aurkb was critical for lung development but was not necessary for postnatal growth and the repair of the adult lung after injury. Deletion of Aurkb in embryonic Sox9+ cells led to the formation of a stunted lung that retained the expression of Sox2 in the proximal airways, as well as Sox9 in the distal tips. While we found no change in cell polarity, we showed that loss of Aurkb or chemical inhibition of Aurkb induced a block of Sox9+ cells in G2/M, likely responsible for the lack of branch bifurcation. This work demonstrates the power of genetic screens in identifying novel regulators of Sox9+ progenitor cells and lung branching morphogenesis.

scholarly journals Matrix metalloproteinases are expressed during ductal and alveolar mammary morphogenesis, and misregulation of stromelysin-1 in transgenic mice induces unscheduled alveolar development.

1995 ◽  
Vol 6 (10) ◽  
pp. 1287-1303 ◽  
Author(s):  
J P Witty ◽  
J H Wright ◽  
L M Matrisian
Keyword(s):  
Basement Membrane ◽  
Transgenic Mice ◽  
Three Dimensional ◽  
Fold Increase ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Myoepithelial Cells ◽  
Stromal Fibroblasts ◽  
Alveolar Development ◽  
Ductal Branching

The matrix-degrading metalloproteinases stromelysin-1, stromelysin-3, and gelatinase A are expressed during ductal branching morphogenesis of the murine mammary gland. Stromelysin-1 expression in particular correlates with ductal elongation, and in situ hybridization and three-dimensional reconstruction studies revealed that stromelysin-1 mRNA was concentrated in stromal fibroblasts along the length of advancing ducts. Transgenic mice expressing an activated form of stromelysin-1 under the control of the MMTV promoter/enhancer exhibited inappropriate alveolar development in virgin females. Ultrastructural analysis demonstrated that the basement membrane underlying epithelial and myoepithelial cells was amorphous and discontinuous compared with the highly ordered basal lamina in control mammary glands. Transgenic mammary glands had at least a twofold increase in the number of cells/unit area and a 1.4-fold increase in the percent of cycling cells by 13 wk of age compared with nontransgenic littermates. In addition, transgenic glands expressed beta-casein mRNA, but not protein, and resembled the proliferative and differentiated state of an animal between 8 and 10 days pregnant. An analysis of metalloproteinase expression in the glands of normal pregnant females demonstrated that the same matrix metalloproteinase family members, including stromelysin-1, were expressed in connective tissue cells surrounding epithelial clusters during the time of lobuloalveolar development. These results suggest that metalloproteinases may assist in remodeling ECM during normal ductal and alveolar branching morphogenesis, and that disruption of the basement membrane by an activated metalloproteinase can affect basic cellular processes of proliferation and differentiation.

scholarly journals Impaired Alveologenesis and Maintenance of Secretory Mammary Epithelial Cells in Jak2 Conditional Knockout Mice

2004 ◽  
Vol 24 (12) ◽  
pp. 5510-5520 ◽  
Author(s):  
Kay-Uwe Wagner ◽  
Andrea Krempler ◽  
Aleata A. Triplett ◽  
Yongyue Qi ◽  
Nicholas M. George ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Prolactin Receptor ◽  
Branching Morphogenesis ◽  
Regulatory Elements ◽  
Conditional Knockout ◽  
Multiple Gestation ◽  
Alveolar Cells ◽  
Signal Transducers ◽  
Conditional Knockout Mice

ABSTRACT Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat). The biological relevance of Jak2-Stat signaling in hormone-responsive adult tissues is difficult to investigate since Jak2 deficiency leads to embryonic lethality. We generated Jak2 conditional knockout mice to study essential functions of Jak2 during mammary gland development. The mouse mammary tumor virus-Cre-mediated excision of the first coding exon resulted in a Jak2 null mutation that uncouples signaling from the prolactin receptor (PRL-R) to its downstream mediator Stat5 in the presence of normal and supraphysiological levels of PRL. Jak2-deficient females were unable to lactate as a result of impaired alveologenesis. Unlike Stat5a knockouts, multiple gestation cycles could not reverse the Jak2-deficient phenotype, suggesting that neither other components of the PRL-R signaling cascade nor other growth factors and their signal transducers were able to compensate for the loss of Jak2 function to activate Stat5 in vivo. A comparative analysis of Jak2-deficient mammary glands with transplants from Stat5a/b knockouts revealed that Jak2 deficiency also impairs the pregnancy-induced branching morphogenesis. Jak2 conditional mutants therefore resemble PRL-R knockouts more closely, which suggested that Jak2 deficiency might affect additional PRL-R downstream mediators other than Stat5a and Stat5b. To address whether Jak2 is required for the maintenance of PRL-responsive, differentiating alveolar cells, we utilized a transgenic strain that expresses Cre recombinase under regulatory elements of the whey acidic protein gene (Wap). The Wap-Cre-mediated excision of Jak2 resulted in a negative selection of differentiated alveolar cells, suggesting that Jak2 is required not only for the proliferation and differentiation of alveolar cells but also for their maintenance during lactation.

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