No abstract

Gene expression can be regulated at multiple levels, including transcription, RNA processing, RNA localization, translation and, finally, RNA turnover. RNA degradation may occur at points along the processing pathway or during translation as it undergoes quality control by RNA surveillance systems. Alternatively, mRNAs may be subject to regulated degradation, often mediated by cis-encoded determinants in the mRNA sequence that, through the recruitment of trans factors, determine the fate of the mRNA. The aim of the present review is to highlight mechanisms of regulated and quality-control RNA degradation in eukaryotic cells, with an emphasis on mammals.

ABSTRACT:Fetal metabolism significantly contributes to the clearance of drugs from the fetus. To understand how the changes in fetal metabolism expected in late gestation alter fetal drug clearance, serial measurements of morphine metabolism were made in the fetal baboon over the latter third of gestation. Clearance and metabolism were evaluated in the context of fetal growth, onset of labor, and the administration of classical enzyme induction agents. Morphine, a probe substrate for the enzyme uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7), was continuously infused to chronically catheterized fetal baboons while measuring morphine, morphine-3-␤-glucuronide, and morphine-6-␤-glucuronide concentrations. In some animals, intermittent infusions of the metabolites provided estimates of metabolite clearance and, hence, the rate of formation of metabolites and metabolic clearance.Overall, metabolic clearance of morphine from the fetus was 27 ؎ 9.0 ml ⅐ min ؊1 or 32% of total clearance. This is similar to the overall clearance in the adult baboon when standardized to weight. No change in any measure of metabolism or clearance of morphine or its glucuronide metabolites was found with gestational age, the presence of labor, or administration of UGT enzyme induction agents. Interpreting these findings using a physiologically based approach suggests that the intrinsic clearance of the fetal liver toward morphine is of sufficient magnitude that fetal hepatic clearance is flow-limited. The implication of a high intrinsic clearance is for significant placento-hepatic first-pass metabolism when drugs are administered to the mother. The previously held view of the "inadequacy of perinatal glucuronidation" needs to be reconsidered.More than 90% of women take some form of prescribed medication during pregnancy (Glover et al., 2003). This high prevalence of drug use by pregnant women underscores the importance of understanding drug disposition in the fetus. The general consensus is that almost all drugs cross the placenta to some extent. Several factors such as protein binding, ionization, fetal metabolism, and active placental transport are known to influence fetal drug exposure (Garland, 1998). However, no comprehensive pharmacokinetic model exists that predicts fetal drug concentrations, let alone drug metabolite concentrations. For the most part, both toxic and direct beneficial effects of an agent occur in the fetus in a dosedependent manner. Thus, models are critical to assess the risk or efficacy of an agent and to optimize the choice of agent for use in pregnancy. The chronically catheterized pregnant baboon provides an animal model with close parallels to human pregnancy (Stark et al., 1989(Stark et al., , 1993(Stark et al., , 1999Daniel et al., 1992;Grieve et al., 1994;Garland et al., 1996Garland et al., , 1998a. The model has considerable utility and direct application to understanding the processes contributing to fetal drug disposition. The studies reported here are part of a larger project to develop a comp...

Epigenetic resetting in germ cells during development de-represses transposable elements (TEs). piRNAs protect fetal germ cells by targeted mRNA destruction and deposition of repressive epigenetic marks. Here, we provide the first evidence for an active piRNA pathway and TE repression in germ cells of human fetal testis. We identify pre-pachytene piRNAs with features of secondary amplification that map most abundantly to the long interspersed element type 1 (L1) family of TEs. L1-ORF1p expression is heterogeneous in fetal germ cells, peaks at mid-gestation and declines concomitantly with increases in piRNAs, nuclear localization of HIWI2 and an increase in H3K9me3. Surprisingly, the same cells with accumulation of L1-ORF1p display highest levels of HIWI2 and H3K9me3. Conversely, the earliest germ cells with high levels of L1-ORF1p express low levels of the chaperone HSP90α. We propose that a subset of germ cells resists L1 expression, whereas L1-expressing germ cells activate the repression pathway that leads to epigenetic silencing of L1 via H3K9me3.