Orla M Conneely — Page 2

PubMed2002

The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear.

Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior. During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates. After formation of the membranous labyrinth, Nor-1 expression in the vestibule is limited to nonsensory epithelial cells localized at the inner edge of the semicircular canals and to the ampullary and utricular walls. In the absence of Nor-1, the vestibular walls fuse together as normal; however, the endolymphatic fluid space in the semicircular canals is diminished and the roof of the ampulla appears flattened due to defective continual proliferative growth of the semicircular canals.

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PubMed2002

Lactoferrin and host defense.

Lactoferrin is a multifunctional member of the transferrin family of nonheme iron-binding glycoproteins. Lactoferrin is found at the mucosal surface where it functions as a prominent component of the first line of host defense against infection and inflammation. The protein is also an abundant component of the specific granules of neutrophils and can be released into the serum upon neutrophil degranulation. While the iron-binding properties were originally believed to be solely responsible for the host defense properties ascribed to lactoferrin, it is now known that other mechanisms contribute to the broad spectrum anti-infective and anti-inflammatory roles of this protein. In this article, current information on the functions and mechanism of action of lactoferrin are reviewed, with particular emphasis on the activities that contribute to this protein's role in host defense. In addition, studies demonstrating that lactoferrin inhibits allergen-induced skin inflammation in both mice and humans, most likely secondary to TNF-alpha (tumor necrosis factor alpha) production, are summarized. Collectively, these results suggest that lactoferrin functions as a key component of mammalian host defense at the mucosal surface.

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PubMed2002

Reproductive functions of progesterone receptors.

The steroid hormone progesterone plays a central role in the reproductive events associated with pregnancy establishment and maintenance. Physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed as two protein isoforms, PR-A and PR-B. Both proteins arise from the same gene and are members of the nuclear receptor superfamily of transcription factors. Since these two isoforms were identified in the early 1970s, extensive controversy has existed regarding the selective contributions of the individual PR proteins to the physiological functions of progesterone. During the past decade, significant progress has been made in this regard using two complimentary approaches. First, analysis of the structural and functional relationships of each isoform using in vitro systems has generated compelling evidence to support the conclusion that PR-A and PR-B have different transcription activation properties when liganded to progesterone. Second, the advent of gene-targeting approaches to introduce subtle mutations into the mouse genome has facilitated the evaluation of the significance of observations made in vitro in a physiological context. Selective ablation of PR-A and PR-B proteins in mice using these technologies has allowed us to address the spatiotemporal expression and contribution of the individual PR isoforms to the pleiotropic reproductive activities of progesterone. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided proof of concept that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are, indeed, reflected in an ability of the individual isoforms to elicit distinct, physiological responses to progesterone. In PR-A knockout mice, in which the expression of the PR-A isoform is selectively ablated (PRAKO), the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect responses of the mammary gland or thymus to progesterone but instead results in severe abnormalities in ovarian and uterine function, leading to female infertility. These tissue-selective activities of PR-B are due to this isoform's ability to regulate a subset of progesterone-responsive target genes in reproductive tissues rather than to differences in its spatiotemporal expression relative to the PR-A isoform. More recent studies using PR-B knockout (PRBKO) mice have shown that ablation of PR-B does not affect ovarian, uterine, or thymic responses to progesterone but rather results in reduced mammary ductal morphogenesis. Thus, PR-A is both necessary and sufficient to elicit the progesterone-dependent reproductive responses necessary for female fertility, while PR-B is required to elicit normal proliferative responses of the mammary gland to progesterone. This chapter will summarize recent progress in our understanding of the selective contribution of the two PR isoforms to progesterone action.

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