Morphogenetic competence of HNF4 alpha-deficient mouse hepatic cells.
OBJECTIVE
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.
Hayhurst
Graham P
GP
Unité de Génétique de la Différenciation, Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France.
Strick-Marchand
Hélène
H
Mulet
Céline
C
Richard
Anne-Françoise
AF
Morosan
Serban
S
Kremsdorf
Dina
D
Weiss
Mary C
MC
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D015820:Cadherins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein