Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme
Todd D. Camenisch, Andrew P. Spicer, Tammy Brehm-Gibson, Jennifer Biesterfeldt, Mary Lou Augustine, Anthony Calabro Jr., Steven Kubalak, Scott E. Klewer, John A. McDonald
Todd D. Camenisch, Andrew P. Spicer, Tammy Brehm-Gibson, Jennifer Biesterfeldt, Mary Lou Augustine, Anthony Calabro Jr., Steven Kubalak, Scott E. Klewer, John A. McDonald
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Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme

Abstract

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.

Authors

Todd D. Camenisch, Andrew P. Spicer, Tammy Brehm-Gibson, Jennifer Biesterfeldt, Mary Lou Augustine, Anthony Calabro Jr., Steven Kubalak, Scott E. Klewer, John A. McDonald

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Ultrastructure of wild-type and Has2–/– E9.5 mouse hearts. Scanning elec...
Ultrastructure of wild-type and Has2–/– E9.5 mouse hearts. Scanning electron micrograph of the external structure of the heart from a wild-type (a–c) and an Has2–/– embryo (d–f). Specimens were viewed from the left side (a and d), the front (b and e), and the right side (c and f). Note the apparent absence of the presumptive right ventricle and outflow tract in the Has2–/– embryo compared with the wild type. Scanning electron microscopy of cross-sections of hearts from wild-type (g and h) and Has2–/– embryos (i and j) reveal a lack of AV cushions and a compacted ventricle wall lacking trabeculations (arrowheads). There is a constriction at the site of the AV canal in the Has2–/– embryo. LV, left ventricle; RV, right ventricle; AoP septum, aortic pulmonary septum. Asterisks indicate left posterior atrial wall. h and j are higher magnifications of g and i, respectively.