Publications by authors named "Hennighausen L"

The enhancer within the long terminal repeats (LTRs) of acquired somatic mouse mammary tumor viruses (MMTV) can activate juxtaposed genes and induce mammary tumors. In contrast, germ line proviral MMTV genomes are integrated in the host genome and considered to be genetically confined transcription units. Here we demonstrate that transcription initiated in an MMTV provirus proceeds into flanking host sequences.

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Male mice lack mammary glands due to the interaction of circulating androgens with local epithelial-mesenchymal signaling in the developing mammary bud. Mammary epithelial cells induce androgen receptor (AR) within the mammary mesenchyme and, in response to androgens, the mesenchyme condenses around the epithelial bud, destroying it. We show that this process involves apoptosis and that, in the absence of parathyroid hormone-related protein (PTHrP) or its receptor, the PTH/PTHrP receptor (PPR1), it fails due to a lack of mesenchymal AR expression.

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Cre-mediated excision of exon 11 of the breast-tumour suppressor gene Brca1 in mouse mammary epithelial cells causes increased apoptosis and abnormal ductal development. Mammary tumour formation occurs after long latency and is associated with genetic instability characterized by aneuploidy, chromosomal rearrangements or alteration of Trp53 (encoding p53) transcription. To directly test the role of p53 in Brca1-associated tumorigenesis, we introduced a Trp53-null allele into mice with mammary epithelium-specific inactivation of Brca1.

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Stat5b gene disruption leads to an apparent growth hormone (GH) pulse insensitivity associated with loss of male-characteristic body growth rates and male-specific liver gene expression (Udy, G. B., Towers, R.

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To control G protein signaling in vivo, we have modified G protein-coupled receptors to respond exclusively to synthetic small molecule agonists and not to their natural agonist(s). These engineered receptors are designated RASSLs (receptor activated solely by a synthetic ligand). A prototype RASSL (Ro1) based on the Gi-coupled K opioid receptor was expressed in transgenic mice under the control of the tetracycline transactivator (tet) system.

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Oxytocin is a nonapeptide hormone that participates in the regulation of parturition and lactation. It has also been implicated in various behaviors, such as mating and maternal, and memory. To investigate whether or not oxytocin (OT) is essential for any of these functions, we eliminated, by homologous recombination, most of the first intron and the last two exons of the OT gene in mice.

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In a manner similar to many other cytokines, treatment of cells with granulocyte CSF (G-CSF) has been shown to induce the tyrosine phosphorylation of the STAT proteins. Activation of Stat1 and Stat5 by G-CSF requires the membrane-proximal cytoplasmic domain of the receptor, including box1 and box2, while G-CSF-stimulated tyrosine phosphorylation of Stat3 also requires a region distal to box 2. In this study, we show that although the membrane-proximal 55 amino acids of the G-CSF receptor are sufficient for activation of Stat5, the maximal rate of Stat5 activation requires an additional 30 amino acids of the cytoplasmic domain.

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STAT5A and STAT5B are two highly related transcription factors encoded by two distinct genes. STAT5A and STAT5B are activated by a broad range of cytokines and growth factors. Although they can be differentially activated, the functional difference between these two molecules relative to their structure is not known.

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The functional inactivation of the tumor susceptibility gene tsg101 in mouse NIH3T3 cells leads to cell transformation and the formation of metastatic tumors in nude mice. We cloned, mapped and sequenced the mouse tsg101 gene and further identified a processed pseudogene that is 98% identical to the tsg101 cDNA. Based on Northern blot analysis, tsg101 is expressed ubiquitously in mouse tissues.

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Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of the Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6. We show that the IL-4 receptor, like other cytokine receptor systems utilizing the common receptor gamma-chain (gammac), is also connected to a signaling pathway that involves STAT5. Both STAT5a and STAT5b become tyrosine-phosphorylated and acquire specific DNA-binding properties in response to IL-4 receptor stimulation in the murine pro-B cell line Ba/F3.

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Prolactin induces mammopoiesis and lactogenesis through the Janus kinase-signal transducers and activators of transcription pathway, with Stat5a being a principal and obligate cytoplasmic and nuclear signaling molecule. Mice from which the Stat5a gene has been deleted fail to develop functional mammary tissue during their first pregnancy. Lobuloalveolar outgrowth is curtailed, and epithelial cells fail to progress to functional differentiation.

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The oxytocin (OT)-neurophysin preprohormone is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. OT is cleaved from its precursor, transported from the magnocellular neurons to the posterior pituitary and secreted during labour and upon the suckling stimulus of pups. OT induces the contraction of myoepithelial cells surrounding the mammary alveoli, which leads to the ejection of milk.

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Studies of C/EBPbeta-deficient mice have demonstrated a pivotal role for this transcription factor in hematopoiesis, adipogenesis, and ovarian function. Here we show that C/EBPbeta is also essential for normal development and function of the mammary gland. Ductal morphogenesis in virgin C/EBPbeta-deficient mice was disrupted, with ducts displaying reduced growth and branching.

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Multistep tumorigenesis proceeds through activation of oncogenes and inactivation of tumor suppressor genes. Initiating oncoproteins induce secondary changes that maintain transformation in the absence of original stimuli. Time-dependent reversal of SV40 T antigen (TAg)-induced hyperplasia was studied using temporally controlled gene expression.

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Extracellular matrix and growth factors cooperate to regulate signaling pathways and gene transcription in adherent cells. However, the mechanism of extracellular matrix signaling is poorly defined. In mammary gland, the expression of milk protein genes is controlled by cross-talk between signals derived from the basement membrane protein, laminin, and the lactogenic hormone, prolactin.

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Stat5a was identified as a prolactin-induced transcription factor but also is activated by other cytokines, including interleukin-2 (IL-2) and IL-7. We have now analyzed the immune system of Stat5a-deficient mice. Stat5a-/- splenocytes exhibited defective IL-2-induced expression of the IL-2 receptor alpha chain (IL-2R alpha), a protein that together with IL-2R beta and the common cytokine receptor gamma chain (gamma(c)) mediates high-affinity IL-2 binding.

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To delete genes specifically from mammary tissue using the Cre-lox system, we have established transgenic mice expressing Cre recombinase under control of the WAP gene promoter and the MMTV LTR. Cre activity in these mice was evaluated by three criteria. First, the tissue distribution of Cre mRNA was analyzed.

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Responses of cells to cytokines typically involve the activation of a family of latent DNA binding proteins, referred to as signal transducers and activators of transcription (STAT) proteins, which are critical for the expression of early response genes. Of the seven known STAT proteins, STAT5 (originally called mammary gland factor) has been shown to be activated by several cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5, which are known to play important roles in growth and differentiation of hematopoietic precursors. In this report we have used mice that are deficient in STAT5A (one of two homologues of STAT5) to study the role of STAT5A in GM-CSF stimulation of cells.

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In a meritorious effort H. de Rothschild compiled in 1899 all publications on mammary gland development and milk--a grand total of 8375 [1]. In the preface to this publication Duclaux states: 'Such a discrepancy between the tremendous efforts and the paltriness of the results--hundreds of scientists and thousands of research years, just to create 200 or 300 pages of truth'.

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The LAR receptor-like protein tyrosine phosphatase is composed of two intracellular tyrosine phosphatase domains and a cell adhesion molecule-like extracellular region containing three immunoglubulin-like domains in combination with eight fibronectin type-III-like repeats. This architecture suggests that LAR may function in cellular signalling by the regulation of tyrosine phosphorylation through cell-cell or cell-matrix interactions. We used gene targeting in mouse embryonic stem cells to generate mice lacking sequences encoding both LAR phosphatase domains.

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Inhibins and activins are members of the transforming growth factor beta (TGFbeta) family. Female mice in which both alleles encoding the inhibin betaB subunit have been deleted are unable to nurse their pups. We have now identified a cause of lactation failure in these mice.

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In situ hybridization was performed with sections obtained from mammary gland at 10 days of lactation and at 1 and 3 days of involution using either digoxigenin-labeled antisense or sense RNA probe in order to localize expression of WDNM1 and ferritin heavy chain mRNA. The WDNM1 gene was predominantly expressed in the layer of secretory epithelial cells surrounding the lumen of mammary gland alveoli. The lower levels of WDNM1 mRNA were observed at involution day 3 compared to involution day 1.

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