Biomedical subjects

Christopher J Ormandy

Publications and source records attributed to Christopher J Ormandy.

22 records · Page 2Linked to original sources

PubMed2002

Y4 receptor knockout rescues fertility in ob/ob mice.

Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4(-/-)) onto the ob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterile ob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of female Y4(-/-),ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4(-/-) and Y4(-/-),ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased in Y4(-/-) and Y4(-/-),ob/ob animals. Y4(-/-) mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP). However, Y4 deficiency had no beneficial effects to reduce body weight or excessive adiposity of ob/ob mice. These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPY-ergic tonus.

Adipose Tissue↗

PubMed2002

Mouse strain-specific patterns of mammary epithelial ductal side branching are elicited by stromal factors.

Variations in mammary ductal side branching patterns are known to occur between different strains of mice and this is related to the rate of spontaneous mammary cancers, which are increased in those strains which show highly side-branched mammary architecture. The cause of the variation in ductal side branching between mouse strains is unknown, but epithelial, stromal, and endocrine factors have been implicated. To define the mammary elements responsible for controlling strain-specific ductal side branching patterns, we formed recombined mammary glands from epithelial and stroma elements taken from highly side-branched 129 and poorly side-branched C57BL/6J mammary glands and transplanted them to Rag1(-/-) hosts on the inbred C57BL/6J background. When 129 epithelium was recombined with C57BL/6J stroma the poorly side-branched C57BL/6J pattern was observed. C57BL/6J epithelium recombined with 129 stroma resulted in development of the highly side- branched pattern, as did 129 epithelium recombined with 129 stroma. All transplants used the same C57BL/6J endocrine background, demonstrating that strain differences in the mammary stroma are responsible for the strain-specific ductal side branching patterns and that strain differences in epithelium or endocrine background play no part. Genes currently known to influence side branching by means of the stroma include activin/inhibin, epidermal growth factor receptor (EGFR), Wnt-2, Wnt-5a, and Wnt-6. Of these, Wnt-5a mRNA expression was decreased in 129 mammary glands compared with C57BL/6J mammary glands, but in F2 129:C57BL/6J animals Wnt-5a mRNA expression level did not correlate with the highly variable side branching patterns observed. These experiments exclude variation in the expression level of known candidate genes as the mechanism responsible. Regardless of underlying mechanism, transplantation without regard to the genetic background of the stromal donor, whether inbred or mixed, will compromise experiments with side branching and associated gene expression endpoints.

Animals↗

PubMed2002

Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development.

Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-beta (C/EBPbeta), was shown previously to result in aberrant ductal morphogenesis and decreased lobuloalveolar development, accompanied by an altered pattern of progesterone receptor (PR) expression. Here, similar changes in the level and pattern of prolactin receptor (PrlR) expression were observed while screening for differentially expressed genes in C/EBPbeta(null) mice. PR patterning was also altered in PrlR(null) mice, as well as in mammary tissue transplants from both PrlR(null) and signal transducer and activator of transcription (Stat) 5a/b-deficient mice, with concomitant defects in hormone-induced proliferation. Down-regulation of PR and activation of Stat5 phosphorylation were seen after estrogen and progesterone treatment in both C/EBPbeta(null) and wild-type mice, indicating that these signaling pathways were functional, despite the failure of steroid hormones to induce proliferation. IGF binding protein-5, IGF-II, and insulin receptor substrate-1 all displayed altered patterns and levels of expression in C/EBPbeta(null) mice, suggestive of a change in the IGF signaling axis. In addition, small proline-rich protein (SPRR2A), a marker of epidermal differentiation, and keratin 6 were misexpressed in the mammary epithelium of C/EBPbeta(null) mice. Together, these data suggest that C/EBPbeta is a master regulator of mammary epithelial cell fate and that the correct spatial pattern of PR and PrlR expression is a critical determinant of hormone-regulated cell proliferation.

Animals↗

PubMedDate not supplied

Prolactin regulates mammary epithelial cell proliferation via autocrine/paracrine mechanism.

Prolactin (PRL) is essential for a number of developmental events in the mammary gland. Work with PRL and PRL receptor knockout mice has shown that PRL indirectly regulates ductal side branching during puberty and directly controls lobuloalveolar development and lactogenesis during pregnancy. Anterior pituitary or placental PRL is thought to be responsible for these functions via an endocrine mechanism; however, PRL is also produced in a number of extrapituitary sites including the mammary gland. The physiologic relevance of mammary PRL remains unknown. In this study we utilized mammary recombination in Rag1(-/-) hosts, to determine whether mammary PRL plays a role in the regulation of mammary gland development. Mammary glands formed with the PRL gene deleted from either the epithelium, stroma, or both displayed normal development, on the basis of whole mount and hematoxylin and eosin histology, during puberty and lactation. At the end of pregnancy, a 2.8-fold decrease in bromodeoxyuridine incorporation was observed in the epithelial cells of mammary glands formed using PRL knockout epithelium compared with those formed using wildtype epithelium. No balancing alteration in the rates of apoptosis was detected. Thus, mammary-derived PRL influences mammary epithelial cell proliferation via an autocrine/paracrine mechanism, establishing a physiologic function for mammary PRL during mammopoiesis.

Animals↗