Abstract. Isoform-specific antibodies to TGF01, TGF02, and TGF03 proteins were generated and have been used to examine the expression of these factors in the developing mouse embryo from 12 .5-18 .5 d post coitum (d.p.c.). These studies demonstrate the initial characterization of both TGFs2 and /33 in mammalian embryogenesis and are compared with TGF01. Expression of one or all three TGFO proteins was observed in many tissues, e.g., cartilage, bone, teeth, muscle, heart, blood vessels, lung, kidney, gut, liver, eye, ear, skin, and nervous tissue. Furthermore, all three TGFO proteins demonstrated discrete cell-specific patterns of expression at various stages of development and the wide variety of tissues expressing TGF0 proteins represent all three primary embryonic germ lay-P OLYPEPTIDE growth factors such as the 0-type transforming growth factors (TGFos) mediate many cellcell interactions that occur during embryonic development (reviewed in Mercola and Stiles, 1988;Whitman and Melton, 1989;Nilsen-Hamilton, 1990). Complementary DNA clones havebeen isolated for five TGFS species (TGFos 1-5); however, purified or recombinant protein has been obtained only for TGF$s 1-3 (Derynck et al., 1985(Derynck et al., , 1988Madisen et al., 1988; ten Dijke et al., 1988;Jakowlew et al., 1988). Moreover, only TGFos 1-3 have been found in mammals. The molecular structures of TGF01, (32, and 03 are very similar in that each polypeptide is synthesized as a prepro monomeric protein and is cleaved to yield a 112-amino acid polypeptide that remains associated withthe latent (pro) portion ofthe molecule (reviewed in Lyons and or Miller et al., 1990 . Biologically active TGF0 protein results from dimerization of the monomers (usually homodimers) and release of the latent peptide portion . Overall, the mature region of the TGF03 protein has -80% identity to the mature regions of both TGFO 1 and TGF02, however, the NH2-terminal or precursor regions of these three molecules Melissa Jones' present address is Department of Chemistry, Hendrix College, Conway, AR 72032 .

The liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. In the setting of cholesterol excess, LXR activation induces the expression of a battery of genes involved in cholesterol efflux 1, facilities cholesterol esterification by promoting fatty acid synthesis 2, and inhibits cholesterol uptake by the low-density lipoprotein receptor (LDLR)3. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways, are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as one mediator of this effect. Hepatic LeXis expression is robustly induced in response to western diet feeding or pharmacologic LXR activation. Raising or lowering the levels of LeXis in liver affects the expression of cholesterol biosynthetic genes, and the levels of cholesterol in the liver and plasma. LeXis interacts with and affects the DNA interactions of Raly, a heterogeneous ribonucleoprotein that is required for the maximal expression of cholesterologenic genes in mouse liver. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating sterol homeostasis.

Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell-type specificity of nuclear receptors remain poorly understood. Here we outline a role for a non-coding RNA in modulating the cell type-specific actions of LXRs, sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the critical cholesterol efflux gene Abca1. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands our understanding of the mechanisms underlying cell-type selective actions of nuclear receptors in physiology and disease.

The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy.