Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1.
Asymmetric expression of Sonic hedgehog (Shh) in Hensen's node of the chicken embryo plays a key role in the genetic cascade that controls left-right asymmetry, but its involvement in left-right specification in other vertebrates remains unclear. We show that mouse embryos lacking Shh display a variety of laterality defects, including pulmonary left isomerism, alterations of heart looping, and randomization of axial turning. Expression of the left-specific gene Lefty-1 is absent in Shh(-/-) embryos, suggesting that the observed laterality defects could be the result of the lack of Lefty-1. We also demonstrate that retinoic acid (RA) controls Lefty-1 expression in a pathway downstream or parallel to Shh. Further, we provide evidence that RA controls left-right development across vertebrate species. Thus, the roles of Shh and RA in left-right specification indeed are conserved among vertebrates, and the Shh and RA pathways converge in the control of Lefty-1.
Tsukui
T
T
The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, CA 92037-1099, USA.
Capdevila
J
J
Tamura
K
K
Ruiz-Lozano
P
P
Rodriguez-Esteban
C
C
Yonei-Tamura
S
S
Magallón
J
J
Chandraratna
R A
RA
Chien
K
K
Blumberg
B
B
Evans
R M
RM
Belmonte
J C
JC
D000818:Animals; D001483:Base Sequence; D002642:Chick Embryo; D000013:Congenital Abnormalities / Q000209:etiology*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D055458:Left-Right Determination Factors; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014212:Tretinoin / Q000502:physiology*
D053823:Hedgehog Proteins; D055458:Left-Right Determination Factors; D011506:Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014212:Tretinoin