Lefty (protein)

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This article is about the protein Lefty. For other uses, see Lefty (disambiguation).
Chr. 1 q42.1
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StructuresSwiss-model
DomainsInterPro
left-right determination factor 2
Identifiers
Symbol
Chr. 1 q42.1
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StructuresSwiss-model
DomainsInterPro

Lefty (left-right determination factors) are a class of

lungs.[2]

History

Lefty, a divergent member of the transforming growth factor-β (

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.[4]

Function

A simplified depiction of the gradients of nodal and lefty in the mouse embryo.

Lefty proteins function as an antagonist of the

Nodal Signaling or TGF beta signaling pathway for more information on the nodal signaling pathway.)[6]

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.,

Nodal Signaling results in the patterning of the embryo and left-right asymmetry.[7]

Clinical significance

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).

endometrial bleeding.[8][9]

Lefty-1

Lefty-1 is a regulatory gene that plays a vital role in the determination of the left-right internal asymmetry observed in mammals. The lefty-1 protein works in tandem with two other genes: lefty-2 and nodal. As the primitive node migrates towards the cranial end of the embryo during development, its cilia preferentially sling lefty-2 and nodal towards the left side of the embryo.[10] These two genes encode for “leftness”, and initiate the formation of the heart, spleen, and other internal organs that are found on the left side in a typical human being. Lefty-1 protein can be viewed as a barrier between the left and right portions of the embryo that prevents the diffusion of lefty-2 and nodal to the right side. This ensures that the left-determining molecules are confined to their correct developmental domain. A variety of defects were observed in mice that had lefty-1 deleted, including left pulmonary isomerism, situs inversus, and atrial septal defect [2]. The high incidence of left pulmonary isomerism in the knockout mice indicates that lefty-1 itself is not involved in encoding for leftness, but simply ensures the correct compartmentation of the left-determining molecules. In the absence of the lefty-1 barrier, lefty-2 and nodal are free to diffuse to the right side and initiate the development of a left lung that was meant to be limited to the left side of the thoracic cavity.

References

  1. ^
    S2CID 20557143
    .
  2. S2CID 5666974
    .
  3. S2CID 4345275
    .
  4. PMID 10053005
    .
  5. ^ a b Carlson, Bruce M. "Formation of Germ Layers and Early Derivatives." Human Embryology and Developmental Biology. Philadelphia, Pennsylvania: Mosby/Elsevier, 2009. 91-95. Print.
  6. PMID 20066122
    .
  7. PMID 17646095
    .
  8. PMID 9153275
    .
  9. PMID 15704472
    .
  10. S2CID 6379844
    .

Further reading

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