Lefty (protein)

left-right determination factor 1
Identifiers
Symbol	LEFTY1
Alt. symbols	LEFTB
Entrez	10637
HUGO	6552
OMIM	603037
RefSeq	NM_020997
UniProt	O75610
Other data
Locus	Chr. 1 q42.1

left-right determination factor 2
Identifiers
Symbol	LEFTY2
Alt. symbols	TGFB4, EBAF
Entrez	7044
HUGO	3122
OMIM	601877
RefSeq	NM_003240
UniProt	O00292
Other data
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.)

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Wikipedia