The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Abstract

Development of the mammalian embryo relies upon nutritive functions fulfilled by the visceral endoderm and then by the liver (1). A part of these functions is accomplished by nutrient carrier proteins of the albumin gene family, a multigene locus expressed by the liver and subject to precise developmental controls. One albumin-related gene, the ␣ 1 -fetoprotein (AFP) 1 gene, is activated at the onset of liver differentiation and operates tightly coupled with liver growth (2, 3). In 1988, our group circumscribed a proximal AFP promoter element essential to AFP gene activity in hepatocytes, and distinct from promoter components regulating the other albumin loci (4). The AFP-specific activator was then identified as orphan receptor fetoprotein transcription factor (5-7), so named for its first identified target locus (genome data base nomenclature, 2 NR5A2 in the nuclear receptor nomenclature, Ref. 9); also referred to as LRH1 or CPF). FTF belonged to a primitive class of nuclear receptors and emerged as a critical lead to connect AFP gene activation with early embryonic growth and differentiation processes.Subsequent studies indicated that developmental FTF functions even preceded its activation of the AFP locus in hepatocytes. In situ hybridization analysis in the mouse at embryonic day 8 -9 showed abundant FTF transcripts in the foregut endoderm, before liver morphogenesis (10). Characterization of the FTF gene promoter also revealed a cluster of regulatory motifs conserved in distant species and potential targets of cell lineage specification factors (11). Among these were three proximal binding sites for GATA factors, known to be essential for visceral endoderm function (12, 13). Furthermore, three HNF genes important to liver differentiation, HNF1␣, HNF4␣, and HNF3␤, were found to each contain double FTF-binding sites in their proximal promoter and to be activated by FTF in transfection assays (11). Thus, a pivotal role was suggested for FTF in a transcriptional cascade using determination factors to activate FTF in prehepatic endodermal cells, and then using FTF to drive AFP and other effectors of the hepatic program.

LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

“…Since conventional knockout of LRH-1 is embryonic-lethal (Pare et al 2004;Gu et al 2005), we used a tamoxifeninducible estrogen receptor-cre system to eliminate LRH-1 in adult tissues, including the pancreas. Mice homozygous for the floxed Lrh1 allele and heterozygous for the ROSA26-ER-cre allele showed no overt abnormalities.…”

“…LRH-1 has high constitutive transcriptional activity, and while it can bind to various phospholipids (Lee and Moore 2008), it remains unclear whether these are physiologic ligands. LRH-1 is present during the earliest stages of development and in embryonic stem cells, where it maintains pluripotency (Pare et al 2004;Gu et al 2005;Heng et al 2010). In adults, LRH-1 is abundantly expressed in endoderm-derived enterohepatic tissues (Rausa et al 1999), where it regulates genes involved in cholesterol, fatty acid, and bile acid homeostasis, and intestinal epithelial cell renewal (Fayard et al 2004;Lee and Moore 2008).…”

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

“…This nuclear receptor plays important developmental functions in the mouse, as demonstrated by the genetic dissection of LRH-1 KO mice (Falender et al, 2003;Pare et al, 2004). LRH-1À/À mice die at e6.5-7.5, due to profound developmental defects, such as impaired node formation and gastrulation (Pare et al, 2004).…”

“…This nuclear receptor plays important developmental functions in the mouse, as demonstrated by the genetic dissection of LRH-1 KO mice (Falender et al, 2003;Pare et al, 2004). LRH-1À/À mice die at e6.5-7.5, due to profound developmental defects, such as impaired node formation and gastrulation (Pare et al, 2004). During adulthood, LRH-1 plays important roles in cholesterol and lipid homeostasis by controlling the expression of genes involved in these metabolic pathways (for a review see Fayard et al, 2004).…”

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

“…Inactivation of LRH-1 leads to early embryonic lethality at the epiblast stage due to the loss of pluripotency of embryonic stem cells (Pare et al 2004;Gu et al 2005). In adult tissues, LRH-1 mRNA can be detected in the liver, small intestine, adrenal gland, granulosa cells in the ovary, pre-adipocytes and testis .…”