Smad5 is essential for left-right asymmetry in mice.
Left-right (L-R) asymmetry of the vertebrate body plan is established from an originally morphologically symmetric embryo. Recent studies have implicated several TGF-beta family signaling proteins (i.e., nodal, lefty-1, lefty-2, activin receptor type IIB, and Smad2) in L-R axis determination in the mouse. However, the genetic pathways underlying L-R patterning are still unclear. Smad5 is a downstream component in the TGF-beta family signaling cascade, and lack of Smad5 results in embryonic lethality between E9.5 and E11.5. In this report, we demonstrate that Smad5 mutant embryos have defects in heart looping and embryonic turning which are the first signs of L-R asymmetry in mice. To gain more insights into the molecular basis of the laterality defects in the Smad5-deficient embryos, we examined the expression of lefty-1, lefty-2, nodal, and Pitx2 since the asymmetric expression of these genes always closely correlates with the direction of heart looping and embryonic turning. In the absence of Smad5, lefty-1 was expressed at very low or undetectable levels, while nodal, lefty-2, and Pitx2 were expressed bilaterally. These data suggest that Smad5 is upstream of lefty-1, nodal, and lefty-2, and as a consequence also of Pitx2, and Smad5 is essential for L-R axis determination.
Chang
H
H
Department of Pathology, Program in Developmental Biology, Houston, Texas, 77030, USA.
Zwijsen
A
A
Vogel
H
H
Huylebroeck
D
D
Matzuk
M M
MM
D000818:Animals; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D005318:Fetal Heart / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D017403:In Situ Hybridization; D055458:Left-Right Determination Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D051902:Smad5 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D000097577:Homeobox Protein PITX2
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D055458:Left-Right Determination Factors; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D010750:Phosphoproteins; D051902:Smad5 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097577:Homeobox Protein PITX2; C526008:Nodal protein, mouse; C497798:Smad5 protein, mouse; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3