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. 2000 Jan 15;14(2):152-7.

An essential role in liver development for transcription factor XBP-1

A M Reimold  1 , A Etkin, I Clauss, A Perkins, D S Friend, J Zhang, H F Horton, A Scott, S H Orkin, M C Byrne, M J Grusby, L H Glimcher
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An essential role in liver development for transcription factor XBP-1

A M Reimold et al. Genes Dev. .

Abstract

XBP-1 is a CREB/ATF family transcription factor highly expressed in hepatocellular carcinomas. Here we report that XBP-1 is essential for liver growth. Mice lacking XBP-1 displayed hypoplastic fetal livers, whose reduced hematopoiesis resulted in death from anemia. Nevertheless, XBP-1-deficient hematopoietic progenitors had no cell-autonomous defect in differentiation. Rather, hepatocyte development itself was severely impaired by two measures: diminished growth rate and prominent apoptosis. Specific target genes of XBP-1 in the liver were identified as alphaFP, which may be a regulator of hepatocyte growth, and three acute phase protein family members. Therefore, XBP-1 is a transcription factor essential for hepatocyte growth.

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Figures

Figure 1
Figure 1
Disruption of the XBP-1 gene. (A) Parts of XBP-1 exons 1 and 2 were deleted and replaced by the neo resistance gene, in the opposite orientation from XBP-1. (B) Southern blotting of genomic DNA from yolk sacs of XBP-1 +/+, +/−, and −/− embryos. (C) Northern blot of whole embryo RNA from XBP-1 +/+ and −/− embryos, probed with 32P-labeled XBP-1 coding region cDNA. (D) Western blot of nuclear cell extracts made from XBP-1 +/+ and −/− fetal livers and probed with XBP-1 monoclonal antibody. (E) Diminished survival of XBP-1−/− embryos seen in offspring of XBP-1+/− × XBP-1+/− matings genotyped by Southern blotting of genomic DNA. No live XBP-1−/− embryos were identified past E14.5. (ND) Not determined.
Figure 2
Figure 2
Liver hypoplasia and anemia in XBP-1-deficient embryos. (A) Hypoplasia of E13.5 XBP-1−/− embryonic livers (middle and left) compared to a XBP-1+/+ littermate control (right). (B,C) Sections of E14.5 +/+ and −/− livers, hematoxylin–eosin stain, 200× magnification. (D) Peripheral blood counts of +/+ and −/− E14.5 and E11.5 embryos. (E,F) Cytospin preparations of blood from E13.5 +/+ and −/− embryos. Nucleated red blood cells represent cells of yolk sac origin; nonnucleated cells derive from liver hematopoiesis.
Figure 3
Figure 3
XBP-1 expression during liver growth. In situ hybridization of a wild-type E10.5 embryo showing XBP-1 signal in the developing liver. (L) Liver; (H) Heart.
Figure 4
Figure 4
Reduced growth rate and increased apoptosis in XBP-1-deficient livers. (A,B) BrdU labeling of E13.5 XBP-1+/+ and XBP-1−/− embryos. (C,D) Higher power views. The −/− liver (L) is smaller in size and labels less intensely than the +/+ control. (E,F) Congo red staining of E13.5 livers. Arrows indicate morphologically apoptotic cells, which were mainly hematopoietic cells in +/+ samples and hepatocytes in −/− samples. (G,H) TUNEL staining (in red) of E13.5 +/+ and −/− livers.
Figure 5
Figure 5
XBP-1 induction in the acute phase response. (A) Gene induction after partial hepatectomy. Total cellular RNA collected in a time course after partial hepatectomy in +/+ mice was probed sequentially with the cDNAs for XBP-1, C/EBPβ, and control β2 microglobulin. (B) Northern blot of mRNA prepared from +/+ (E12.5 or E13.5) or −/− (E13.5) fetal livers, or from the embryo torsos with the livers removed (body). The blot was sequentially hybridized with probes for α1AT, αFP, transthyretin, apoA-1, vitamin D binding protein (VDBP), C-reactive protein (CRP), serum amyloid P (SAP), and γ-actin. (C) Transfections of an α1AT reporter construct or an α1AT reporter containing a mutation of the −1100-bp presumptive XBP-1 binding site (mut α1AT; the ACGT core changed to GTAG) (Clauss et al. 1996), along with an XBP-1 expression plasmid (XBP) or a frameshifted mutant XBP-1 plasmid (XBP-Δ) (Reimold et al. 1996b).
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