Keratins regulate yolk sac hematopoiesis and vasculogenesis through reduced BMP-4 signaling.
Keratin intermediate filament proteins form the major cytoskeleton in all embryonic and adult epithelia. Increasing evidence suggests that keratins, besides their primary cytoskeletal function, can act as scaffolds which locally regulate cell growth and survival in epithelial cells. Many of these functions, however, are not understood in full, owing to keratin redundancy. We have recently created mice which lack all keratins and found that keratins act upstream of mTOR signaling to regulate protein biosynthesis via GLUT localization. Here, we report that keratins are necessary to maintain adhesion between endodermal and mesodermal cell layers of the yolk sac. As a consequence, keratin(-/-) embryos suffer from reduced yolk sac hematopoiesis and vasculogenesis. Pathway analysis revealed a reduction of the hedgehog target Foxf1 in yolk sac mesoderm of keratin(-/-) embryos, and subsequent reduction of BMP-4 and P-p38 MAPK. These defects may be caused by the overall reduction in protein biosynthesis and diminished adhesion. Our data show for the first time that keratins are necessary for the differentiation of a non-epithelial cell lineage through a combination of mechanical and signaling mechanisms.
Vijayaraj
Preethi
P
Institute of Physiological Chemistry, Division of Cell Biochemistry, Bonner Forum Biomedizin and LIMES-Institute, Rheinische Friedrich-Wilhelms-Universität, Nussallee 11, 53115 Bonn, Germany.
Kroeger
Cornelia
C
Reuter
Ursula
U
Hartmann
Dieter
D
Magin
Thomas M
TM
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D006410:Hematopoiesis; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D015017:Yolk Sac / Q000166:cytology / Q000378:metabolism*
D055415:Bone Morphogenetic Protein 4; D007633:Keratins