BACKGROUND/AIMS: To specify roles of HNF 4 alpha in mouse liver development, we have analyzed the ex vivo morphogenetic potential of HNF4 alpha-null embryonic hepatic cells. METHODS: Using mice with floxed or deficiency alleles of HNF4 alpha, hepatic cells lacking this transcription factor were explanted into primary culture and derived into cell lines. RESULTS: Contrary to behavior in vivo where HNF4 alpha-null liver cells fail to show normal polarity and epithelialization, e18.5 hepatic cells in primary culture from mutant embryos show restoration of apical expression of tight junction protein-1 and of transcripts for E-cadherin. Clones of control and HNF4 alpha-null cell lines were indistinguishable, even when differentiation of bile canalicular formation was induced. HNF4 alpha-null and control cell lines showed similar potential to colonize livers of the murine ALB-uPA/SCID model of liver regeneration, but null cells formed only bile ducts and not clusters of hepatocytes. Finally, analysis of mutant embryonic livers revealed a transcriptional signature consistent with a stress response, which could underlie the morphogenetic defects observed in vivo. CONCLUSIONS: We conclude that the lack of epithelialization characteristic of the HNF4 alpha-null embryonic liver is due, at least in part, to non-cell autonomous defects, and that null cells do not suffer intrinsic defects in polarization.
BACKGROUND/AIMS: To specify roles of HNF 4 alpha in mouse liver development, we have analyzed the ex vivo morphogenetic potential of HNF4 alpha-null embryonic hepatic cells. METHODS: Using mice with floxed or deficiency alleles of HNF4 alpha, hepatic cells lacking this transcription factor were explanted into primary culture and derived into cell lines. RESULTS: Contrary to behavior in vivo where HNF4 alpha-null liver cells fail to show normal polarity and epithelialization, e18.5 hepatic cells in primary culture from mutant embryos show restoration of apical expression of tight junction protein-1 and of transcripts for E-cadherin. Clones of control and HNF4 alpha-null cell lines were indistinguishable, even when differentiation of bile canalicular formation was induced. HNF4 alpha-null and control cell lines showed similar potential to colonize livers of the murineALB-uPA/SCID model of liver regeneration, but null cells formed only bile ducts and not clusters of hepatocytes. Finally, analysis of mutant embryonic livers revealed a transcriptional signature consistent with a stress response, which could underlie the morphogenetic defects observed in vivo. CONCLUSIONS: We conclude that the lack of epithelialization characteristic of the HNF4 alpha-null embryonic liver is due, at least in part, to non-cell autonomous defects, and that null cells do not suffer intrinsic defects in polarization.
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Authors: K Yamagata; H Furuta; N Oda; P J Kaisaki; S Menzel; N J Cox; S S Fajans; S Signorini; M Stoffel; G I Bell Journal: Nature Date: 1996-12-05 Impact factor: 49.962
Authors: M A Hyatt; D S Gardner; S Sebert; V Wilson; N Davidson; Y Nigmatullina; L L Y Chan; H Budge; M E Symonds Journal: Reproduction Date: 2010-11-02 Impact factor: 3.906
Authors: Siyeon Rhee; Mara-Isel Guerrero-Zayas; Mary C Wallingford; Pablo Ortiz-Pineda; Jesse Mager; Kimberly D Tremblay Journal: PLoS One Date: 2013-03-15 Impact factor: 3.240
Authors: Luis F Menezes; Fang Zhou; Andrew D Patterson; Klaus B Piontek; Kristopher W Krausz; Frank J Gonzalez; Gregory G Germino Journal: PLoS Genet Date: 2012-11-29 Impact factor: 5.917