Disease relevance of LEFTY1

• Tet responsive and adenovirus based constructs for regulated in vivo expression of Lefty [1].
• Role of EBAF/Lefty in implantation and uterine bleeding [2].

High impact information on LEFTY1

• In addition, Nodal signaling is dependent on coreceptors of the EGF-CFC family and antagonized by the Lefty and Cerberus families of secreted factors [3].
• Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development [4].
• Here we test whether Lefty1 is a direct target of Oct3/4 [5].
• We identified an ES cell-specific enhancer upstream of the Lefty1 promoter that contains binding sites for Oct3/4 and Sox2 [5].
• Here, we show that Nodal and Furin are initially co-expressed in the primitive endoderm together with a subset of DVE markers such as Lefty1 and Hex [6].

Biological context of LEFTY1

• We now report characterization of two Lefty homologues, LEFTY A and LEFTY B, separated by approximately 50 kb on chromosome 1q42 [4].
• The presence of FAST-binding sites in the LEFTY1 enhancer (and their absence in lefty1) contributes to the difference [7].
• RESULTS: The human LEFTY locus comprises two functional genes (LEFTY1 and LEFTY2) and a putative pseudogene [7].
• Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor [8].
• The secreted TGFbeta factor Lefty antagonizes Nodal signaling during vertebrate embryogenesis, but how it does so has been a mystery [9].

Anatomical context of LEFTY1

• In contrast to mouse lefty1, which is expressed predominantly in the floor plate under the control of a right side-specific silencer, human LEFTY1 is expressed mainly in left lateral plate mesoderm under the control of an ASE-like left side-specific enhancer [7].
• Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3 [10].
• Expression analysis indicates that the early expression of nodal, BMP2/4 and lefty is restricted to the oral ectoderm reflecting their role in providing positional information along the oral-aboral axis of the embryo [11].
• Furthermore, adding lefty-1, a nodal antagonist, to the blastoderm inhibited the expression of SMA, and nodal plus BMP antagonist up-regulated the expression of SMA in cultured posterior epiblast [12].

Associations of LEFTY1 with chemical compounds

• In this model, Lefty is regulated by the dose of doxycycline [1].
• To drive the expression of Lefty, we have placed Lefty under control of a tetracycline-responsive promoter which responds to a sequence variant of the reversed tet transcriptional activator (rtTA), rtTA2S-M2 [1].

Regulatory relationships of LEFTY1

• Moreover, lefty inhibits CTGF and collagen mRNA synthesis and increases collagenolysis and elastolysis and as a result of these actions, lefty significantly reduces the amount of collagen deposited in tissues [13].
• Here, we show that TGF-beta signaling is inhibited by lefty, a novel member of the TGF-beta superfamily [8].

Other interactions of LEFTY1

• This study shows that nodal and the inhibitors of Nodal signaling, lefty-A and lefty-B, are down-regulated very early upon differentiation [10].
• Moreover, lefty inhibited the events that lie downstream from R-Smad phosphorylation, including heterodimerization of R-Smad proteins with Smad4 and nuclear translocation of the R-Smad.Smad4 complex [8].
• The action of lefty does not appear to depend on protein synthesis, including synthesis of inhibitory Smad proteins [8].
• Similarly, lefty inhibited both BMP-mediated Smad5 phosphorylation and gene transcription [8].
• Homeostasis of extracellular matrix by TGF-beta and lefty [13].

Analytical, diagnostic and therapeutic context of LEFTY1

• Microarray analysis has shown a member of the transforming growth factor (TGF)-beta superfamily, Lefty, to be the single most abundant inhibitor in stem cells and in maternal decidua that supports embryo implantation [14].

References