Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.
We identified hyaluronan synthase-2 (Has2) as a likely source of hyaluronan (HA) during embryonic development, and we used gene targeting to study its function in vivo. Has2(-/-) embryos lack HA, exhibit severe cardiac and vascular abnormalities, and die during midgestation (E9.5-10). Heart explants from Has2(-/-) embryos lack the characteristic transformation of cardiac endothelial cells into mesenchyme, an essential developmental event that depends on receptor-mediated intracellular signaling. This defect is reproduced by expression of a dominant-negative Ras in wild-type heart explants, and is reversed in Has2(-/-) explants by gene rescue, by administering exogenous HA, or by expressing activated Ras. Conversely, transformation in Has2(-/-) explants mediated by exogenous HA is inhibited by dominant-negative Ras. Collectively, our results demonstrate the importance of HA in mammalian embryogenesis and the pivotal role of Has2 during mammalian development. They also reveal a previously unrecognized pathway for cell migration and invasion that is HA-dependent and involves Ras activation.
Camenisch
T D
TD
Samuel C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259, USA.
Spicer
A P
AP
Brehm-Gibson
T
T
Biesterfeldt
J
J
Augustine
M L
ML
Calabro
A
A
Kubalak
S
S
Klewer
S E
SE
McDonald
J A
JA
D000818:Animals; D001483:Base Sequence; D002465:Cell Movement / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005318:Fetal Heart / Q000196:embryology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D014453:Glucuronosyltransferase / Q000235:genetics / Q000502:physiology*; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning
D017931:DNA Primers; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases