|left-right determination factor 1|
|Locus||Chr. 1 q42.1|
|left-right determination factor 2|
|Alt. symbols||TGFB4, EBAF|
|Locus||Chr. 1 q42.1|
Lefty (left-right determination factors) refers to proteins that are closely related members of the TGF-beta family of growth factors. These proteins are secreted and play a role in left-right asymmetry determination of organ systems during development. Mutations of the genes encoding these proteins have been associated with left-right axis malformations, particularly in the heart and lungs.
Lefty, a divergent member of the transforming growth factor-β (TGF beta) superfamily of proteins, was originally discovered in the Hamada lab at the Osaka University using deletion screening of cDNA libraries in P19 embryonic carcinoma cells to find clones that did not differentiate when induced to differentiate using retinoic acid. From these screens, researchers found one gene that was a tentative member of the TGF-beta superfamily that was predominantly expressed on the left side the embryo and aptly named it lefty. Like other members of the TGF-beta superfamily, lefty is synthesized as a preproprotein, meaning that the protein is proteolytically cleaved and excreted to produce the active form of the protein. However, lefty has only 20-25% sequence similarity with other members of the TGF-beta superfamily. Lefty is conserved in all vertebrates and many species have more than one homologue. Humans and mice, for instance have two homologues, Lefty 1 and Lefty 2, whose differential expression leads to distinct purposes while the mechanism of action is conserved.
Lefty proteins function as an antagonist of the Nodal Signaling pathway. Nodal is another signaling protein which is responsible for gastrulation, left-right patterning and induction of the primitive node. As NODAL protein diffuse through an embryo, it triggers Nodal Signaling within tissues with the required receptors and coreceptors. Activated nodal signaling leads to the transcription of the lefty gene. The protein is then expressed, proteolytically cleaved, and finally secreted. Secreted lefty binds to EGC-CFC proteins like one-eyed pinhead in zebrafish keeping the essential cofactor from associating with NODAL/ Activin-like receptor complex. This will effectually block Nodal Signaling. During induction of the primitive streak, lefty confines Nodal activity to the posterior end of the embryo, establishing a posterior signaling center and inducing the formation of the primitive streak and mesoderm. (See Nodal Signaling or TGF beta signaling pathway for more information on the nodal signaling pathway.)
There are many differences between the left and right sides, including heart and lung positioning. Mutations in these genes cause incorrect positioning of these organs (e.g., situs inversus), or in the case of constitutively inactive lefty, the embryo becomes entirely mesoderm and fails to pattern or develop. During vertebrate development, lefty proteins regulate left-right asymmetry by controlling the spatiotemporal influence of the NODAL protein. Lefty1 in the ventral midline prevents the Cerebrus (paracrine factor or "Caronte") signal from passing to the right side of the embryo. This spatiotemporal control is achieved by using two sources of excreted lefty. While lefty is produced in response to activated nodal signaling, it is also produced and secreted in the anterior visceral endoderm (AVE). The balance of lefty from the AVE and from Nodal Signaling results in the patterning of the embryo and left-right asymmetry.
Proper functioning of Lefty is crucial to the proper development of the heart, lungs, spleen, and liver. Mutations in Lefty, called Lefty-A, are associated with left-right patterning defects. This mutation may cause congenital heart defects due to malformation, interrupted inferior vena cava, and lack of lung asymmetry (left pulmonary isomerism). Lefty2 may play a role in endometrial bleeding.
- Hamada H, Meno C, Watanabe D, Saijoh Y (February 2002). "Establishment of vertebrate left-right asymmetry". Nat. Rev. Genet. 3 (2): 103–13. doi:10.1038/nrg732. PMID 11836504.
- Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K, Ohishi S, Noji S, Kondoh H, Hamada H (August 1998). "lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal". Cell 94 (3): 287–97. doi:10.1016/S0092-8674(00)81472-5. PMID 9708731.
- Meno C, Saijoh Y, Fujii H, Ikeda M, Yokoyama T, Yokoyama M, Toyoda Y, Hamada H (May 1996). "Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos". Nature 381 (6578): 151–5. doi:10.1038/381151a0. PMID 8610011.
- Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont J, Schauer G, Casey B (March 1999). "Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development". Am. J. Hum. Genet. 64 (3): 712–21. doi:10.1086/302289. PMC 1377788. PMID 10053005.
- Carlson, Bruce M. "Formation of Germ Layers and Early Derivatives." Human Embryology and Developmental Biology. Philadelphia, PA: Mosby/Elsevier, 2009. 91-95. Print.
- Schier AF (November 2009). "Nodal Morphogens". Cold Spring Harb Perspect Biol 1 (5): a003459. doi:10.1101/cshperspect.a003459. PMC 2773646. PMID 20066122.
- Takaoka K, Yamamoto M, Hamada H (August 2007). "Origin of body axes in the mouse embryo". Curr. Opin. Genet. Dev. 17 (4): 344–50. doi:10.1016/j.gde.2007.06.001. PMID 17646095.
- Kothapalli R, Buyuksal I, Wu SQ, Chegini N, Tabibzadeh S (May 1997). "Detection of ebaf, a novel human gene of the transforming growth factor beta superfamily association of gene expression with endometrial bleeding". J. Clin. Invest. 99 (10): 2342–50. doi:10.1172/JCI119415. PMC 508072. PMID 9153275.
- Tabibzadeh S (2005). "Role of EBAF/Lefty in implantation and uterine bleeding". Ernst Schering Res. Found. Workshop (52): 159–89. PMID 15704472.
Carlson, Bruce M. "Formation of Germ Layers and Early Derivatives." Human Embryology and Developmental Biology. Philadelphia, PA: Mosby/Elsevier, 2009. 91-95. Print. Sakuma, R., Yi Ohnishi, and C. Meno. "Supplemental Content." National Center for Biotechnology Information. U.S. National Library of Medicine. Web. 31 Mar. 2012.
- left-right determination factor proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University （Hamada Laboratory）