Left–right asymmetric expression of the TGFβ-family member lefty in mouse embryos

Abstract

Examples of lateral asymmetry are often found in vertebrates, such as the heart being on the left side, but the molecular mechanism governing the establishment of this left-right (L-R) handedness is unknown. A diffusible morphogen may determine L-R polarity, but a likely molecule has not so far been identified. Here we report on the gene lefty, a member of the transforming growth factor-beta family, which may encode a morphogen for L-R determination. Lefty protein contains the cysteine-knot motif characteristic of this superfamily and is secreted as a processed form of relative molecular mass 25K-32K. Surprisingly, lefty is expressed in the left half of gastrulating mouse embryos. This asymmetric expression is very transient and occurs just before the first sign of lateral asymmetry appears. In the mouse mutants iv and inv, which cause situs inversus, the sites of lefty expression are inverted, indicating that lefty is downstream of iv and inv. These results suggest that lefty may be involved in setting up L-R asymmetry in the organ systems of mammals.

Mice with mutations in Mahogunin ring finger‐1 (Mgrn1) exhibit abnormal patterning of the left–right axis

“…RNA probes for Nodal, Lefty (which recognizes Lefty1 and Lefty2), and Pitx2 have been described previously (Lowe et al, 1996;Meno et al, 1996;Yoshioka et al, 1998). The Mgrn1 probe was a 420-bp portion of the 3Ј untranslated region (common to all four isoforms) generated by polymerase chain reaction using forward primer CAGTTCCCCCGCACAGGTC and reverse primer AGGAAGGAGCAGGG-TTAGAGTCAG and IMAGE cDNA clone 3481878 as template.…”

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

“…When tested in 293T and BALB/3T3 cell lines, CS1 and CS2 cleavage of mouse Lefty 1 seemed to be regulated in a cell type-dependent manner (Meno et al, 1996). Expression of mouse Lefty 1 and Lefty 2 in Xenopus tissues (animal caps and oocytes) and COS-7 cells resulted in the detection of the short isoform for Lefty 1 and the long isoform for Lefty 2 (Sakuma et al, 2002).…”

“…For FGF8, endocytosis regulates the amount of extracellular protein available for signaling, and the distance the protein can travel from the source of production (Scholpp and Brand, 2004). Receptor availability and extracellular antagonists are powerful dynamic regulators of morphogen gradients (Smith and Harland, 1992;Sasai et al, 1994;Bouwmeester et al, 1996;Goodrich et al, 1996;Meno et al, 1996Meno et al, , 1999Thisse and Thisse, 1999;Cheng et al, 2000;Tanegashima et al, 2000;Larrain et al, 2001;Branford and Yost, 2002;Chang et al, 2003;Harms and Chang, 2003;Zhang et al, 2004). In addition, the preferential degradation of a particular mRNA can contribute to formation of a morphogen gradient.…”

“…Lefty, a divergent member of the TGF␤ family whose transcription is directly regulated by Nodal signaling, is one of the principal extracellular feedback inhibitors of Nodal signaling (Meno et al, 1996(Meno et al, , 1999Thisse and Thisse, 1999;Cheng et al, 2000;Tanegashima et al, 2000;Branford and Yost, 2002;Cha et al, 2006). The current understanding is that Lefty antagonizes Nodal signaling by binding to either the EGF-CFC cofactor directly, or by physically interacting with the Nodal ligand, thereby blocking Nodal-receptor interaction and inhibiting downstream signal transduction (Chen and Shen, 2004;Cheng et al, 2004;Tanegashima et al, 2004).…”

Two closely‐related left‐right asymmetrically expressed genes, lefty‐1 and lefty‐2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos

“…Mouse nodal and a Xenopus homologue, Xnr-1, are expressed in a L-R asymmetric fashion in early embryos (Collignon et al 1996;Lowe et al 1996). We recently identified a divergent TGFbrelated gene, termed lefty, which like nodal, is also expressed in a L-R asymmetric fashion just before the first sign of L-R asymmetry (Meno et al 1996). The expression patterns of lefty and cNR-1/nodal appear to be similar, but there are striking differences; for example, lefty is expressed in one-half of the prospective floor plate, a feature not shared by cNR-1/ nodal.…”