Homeobox gene Hex is essential for onset of mouse embryonic liver development and differentiation of the monocyte lineage.

Disruption of the mouse Hex gene resulted in embryonic lethality around embryonic age (E) 10.5, due to no substantial liver formation. Expression of albumin was detectable in heterozygous (Hex(+/-)) but not in homozygous (Hex(-/-)) [corrected] embryos at E8.5. Instead of liver bud formation at E9.5, a liver-like capsule structure was observed in Hex(-/-) [corrected] embryos. In Hex(-/-) [corrected] mutant liver, we found no hepatocytes but no signs of apoptotic cell death in the area. Expression of transcription factors involved in hepatocyte differentiation, hepatocyte nuclear factor (Hnf)3beta, Hnf6, Hnf4alpha and Hnf1alpha, were restricted to the capsule and internal matrix-like structure in the mutant liver and expression of a subset of these factors were reduced. Hematopoiesis of monocytes was impaired in mutant embryos while erythroid lineage was unaffected. These results indicate that Hex plays an essential role in progenitor cells which commit to the hepatic endoderm and in the hematopoietic differentiation of the monocyte lineage.

[1]  Angela D'Elia,et al.  Expression and function of the homeodomain-containing protein Hex in thyroid cells , 2000, Nucleic Acids Res..

[2]  J. Smith,et al.  Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function. , 2000, Development.

[3]  D. Kioussis,et al.  The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. , 2000, Development.

[4]  D. Stainier,et al.  A role for the extraembryonic yolk syncytial layer in patterning the zebrafish embryo suggested by properties of the hex gene , 1999, Current Biology.

[5]  K. Zaret,et al.  Initiation of mammalian liver development from endoderm by fibroblast growth factors. , 1999, Science.

[6]  T. Tanaka,et al.  Genomic organization and promoter analysis of a mouse homeobox gene, Hex. , 1999, Journal of Biochemistry (Tokyo).

[7]  T. Tanaka,et al.  cDNA cloning and expression of rat homeobox gene, Hex, and functional characterization of the protein. , 1999, The Biochemical journal.

[8]  T. Sasaki,et al.  Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. , 1999, Development.

[9]  T. Yatskievych,et al.  Expression of the homeobox gene Hex during early stages of chick embryo development , 1999, Mechanisms of Development.

[10]  T. Yoneda,et al.  Identification of a novel adenylate kinase system in the brain: cloning of the fourth adenylate kinase. , 1998, Brain research. Molecular brain research.

[11]  A. Wynshaw-Boris,et al.  Cripto is required for correct orientation of the anterior–posterior axis in the mouse embryo , 1998, Nature.

[12]  J. Rossant,et al.  Regulation of a transcription factor network required for differentiation and metabolism. , 1998, Science.

[13]  N. Tamamaki,et al.  Expression of Hex mRNA in early murine postimplantation embryo development , 1998, FEBS letters.

[14]  R. Beddington,et al.  Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. , 1998, Development.

[15]  C. Fletcher,et al.  The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas. , 1997, Developmental biology.

[16]  P. Krieg,et al.  The XHex homeobox gene is expressed during development of the vascular endothelium: overexpression leads to an increase in vascular endothelial cell number , 1997, Mechanisms of Development.

[17]  T. Ley,et al.  Long-range disruption of gene expression by a selectable marker cassette. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Medvinsky,et al.  Definitive Hematopoiesis Is Autonomously Initiated by the AGM Region , 1996, Cell.

[19]  J. R. Coleman,et al.  Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. , 1996, Genes & development.

[20]  B. Wold,et al.  Know Your Neighbors: Three Phenotypes in Null Mutants of the Myogenic bHLH Gene MRF4 , 1996, Cell.

[21]  T. Lints,et al.  Mesoderm‐specific expression of the divergent homeobox gene Hlx during murine embryogenesis , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[22]  S. Cereghini.  Liver‐enriched transcription factors and hepatocyte differentiation , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  K. Zaret,et al.  Molecular genetics of early liver development. , 1996, Annual review of physiology.

[24]  A. Rustighi,et al.  Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells. , 1995, Blood.

[25]  M. Sharpe,et al.  Scatter factor/hepatocyte growth factor is essential for liver development , 1995, Nature.

[26]  E. Scott,et al.  Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. , 1994, Science.

[27]  T. Braun,et al.  A novel NK-related mouse homeobox gene: expression in central and peripheral nervous structures during embryonic development. , 1994, Developmental biology.

[28]  M. Groudine,et al.  An "in-out" strategy using gene targeting and FLP recombinase for the functional dissection of complex DNA regulatory elements: analysis of the beta-globin locus control region. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  R. Hromas,et al.  PCR cloning of an orphan homeobox gene (PRH) preferentially expressed in myeloid and liver cells. , 1993, Biochemical and biophysical research communications.

[30]  E. Wagner,et al.  c-Jun is essential for normal mouse development and hepatogenesis , 1993, Nature.

[31]  A. Ashworth,et al.  HEX: a novel homeobox gene expressed during haematopoiesis and conserved between mouse and human. , 1993, Nucleic acids research.

[32]  E. Buratti,et al.  Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells. , 1992, Nucleic acids research.

[33]  W. C. Forrester,et al.  Inactivation of the human beta-globin gene by targeted insertion into the beta-globin locus control region. , 1992, Genes & development.

[34]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[35]  M. Klemsz,et al.  The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene , 1990, Cell.

[36]  Charles J. Sherr,et al.  The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF 1 , 1985, Cell.

[37]  E. Houssaint.  Differentiation of the mouse hepatic primordium. I. An analysis of tissue interactions in hepatocyte differentiation. , 1980, Cell differentiation.