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1 Department of Bioengineering, 2 Department of Medicine, and 3 Department of Orthopedics, University of California-San Diego, La Jolla, California 92093-0412; and 4 Department of Cell Biology, Duke University, Durham, North Carolina 27710
Tropomodulins are a
family of proteins that cap the slow-growing end of actin filaments.
Erythrocyte tropomodulin (E-Tmod) stabilizes short actin protofilaments
in erythrocytes and caps longer sarcomeric actin filaments in striated
muscles. We report the knockin of the
-galactosidase gene
(LacZ) under the control of the endogenous E-Tmod
promoter and the knockout of E-Tmod in mouse embryonic stem
cells. E-Tmod
/
embryos die around embryonic
day 10 and exhibit a noncontractile heart tube with
disorganized myofibrils and underdevelopment of the right ventricle,
accumulation of mechanically weakened primitive erythroid cells in the
yolk sac, and failure of primary capillary plexuses to remodel into
vitelline vessels, all required to establish blood circulation between
the yolk sac and the embryo proper. We propose a hemodynamic "plexus
channel selection" mechanism as the basis for vitelline vascular
remodeling. The defects in cardiac contractility, vitelline
circulation, and hematopoiesis reflect an essential role for E-Tmod
capping of the actin filaments in both assembly of cardiac sarcomeres
and of the membrane skeleton in erythroid cells that is not compensated
for by other proteins.
erythrocyte tropomodulin; cardiomorphogenesis; hematopoiesis; LacZ; yolk sac; vasculogenesis
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