Lefty (protein)

left-right determination factor 2
left-right determination factor 2
Identifiers
Symbol	LEFTY2
Alt. symbols	TGFB4, EBAF
NCBI gene	7044
HGNC	3122
OMIM	601877
RefSeq	NM_003240
UniProt	O00292
Other data
Locus	Chr. 1 q42.1
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Search for
Structures	Swiss-model
Domains	InterPro

left-right determination factor 1
left-right determination factor 1
Identifiers
Symbol	LEFTY1
Alt. symbols	LEFTB
NCBI gene	10637
HGNC	6552
OMIM	603037
RefSeq	NM_020997
UniProt	O75610
Other data
Locus	Chr. 1 q42.1
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Last updated December 30, 2021

Lefty (left-right determination factors) are a class of proteins that are closely related members of the TGF-beta superfamily of growth factors. These proteins are secreted and play a role in left-right asymmetry determination of organ systems during development.^[1] Mutations of the genes encoding these proteins have been associated with left-right axis malformations, particularly in the heart and lungs.^[2]

History

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.^[3] 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.^[4]

Function

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

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 EGF-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.^[5] (See 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., 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 Cerberus (paracrine factor or "Caronte") signal from passing to the right side of the embryo.^[1] 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.^[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).^[5] Lefty2 may play a role in 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.

Related Research Articles

Symmetry in biology Geometric symmetry in living beings

Symmetry in biology refers to the symmetry observed in organisms, including plants, animals, fungi, and bacteria. External symmetry can be easily seen by just looking at an organism. For example, take the face of a human being which has a plane of symmetry down its centre, or a pine cone with a clear symmetrical spiral pattern. Internal features can also show symmetry, for example the tubes in the human body which are cylindrical and have several planes of symmetry.

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

Primitive streak Structure in early amniote embryogenesis

The primitive streak is a structure that forms in the blastula during the early stages of avian, reptilian and mammalian embryonic development. It forms on the dorsal (back) face of the developing embryo, toward the caudal or posterior end.

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration. apoptosis, cellular homeostasis and other cellular functions. This TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

In the field of developmental biology, regional differentiation is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.

Cripto Protein-coding gene in the species Homo sapiens

Cripto is an EGF-CFC or epidermal growth factor-CFC, which is encoded by the Cryptic family 1 gene. Cryptic family protein 1B is a protein that in humans is encoded by the CFC1B gene. Cryptic family protein 1B acts as a receptor for the TGF beta signaling pathway. It has been associated with the translation of an extracellular protein for this pathway. The extracellular protein which Cripto encodes plays a crucial role in the development of left and right division of symmetry.

Transforming growth factor beta receptor I is a membrane-bound TGF beta receptor protein of the TGF-beta receptor family for the TGF beta superfamily of signaling ligands. TGFBR1 is its human gene.

The transforming growth factor beta (TGF-β) family is a large group of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983. They interact with TGF-beta receptors.

Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.

Growth differentiation factor-3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene. GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 and GDF1.

Cerberus also known as CER1 is a protein that in humans is encoded by the CER1 gene. Cerberus is a signaling molecule which contributes to the formation of the head, heart and left and right asymmetry of internal organs. This gene varies slightly from species to species but its overall functions seem to be similar.

In amniote embryology, the hypoblast, is one of two distinct layers arising from the inner cell mass in the mammalian blastocyst, or from the blastodisc in reptiles and birds. The hypoblast gives rise to the yolk sac, which in turn gives rise to the chorion.

Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.

Nodal is a secretory protein that in humans is encoded by the NODAL gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta (TGF-β) superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the node, in the anterior primitive streak, to lateral plate mesoderm (LPM).

Symmetry breaking in biology is the process by which uniformity is broken, or the number of points to view invariance are reduced, to generate a more structured and improbable state. That is to say, symmetry breaking is the event where symmetry along a particular axis is lost to establish a polarity. Polarity is a measure for a biological system to distinguish poles along an axis. This measure is important because it is the first step to building complexity. For example, during organismal development, one of the first steps for the embryo is to distinguish its dorsal-ventral axis. The symmetry-breaking event that occurs here will determine which end of this axis will be the ventral side, and which end will be the dorsal side. Once this distinction is made, then all the structures that are located along this axis can develop at the proper location. As an example, during human development, the embryo needs to establish where is ‘back’ and where is ‘front’ before complex structures, such as the spine and lungs, can develop in the right location. This relationship between symmetry breaking and complexity was articulated by P.W. Anderson. He speculated that increasing levels of broken symmetry in many-body systems correlates with increasing complexity and functional specialization. In a biological perspective, the more complex an organism is, the higher number of symmetry-breaking events can be found. Without symmetry breaking, building complexity in organisms would be very difficult.

The nodal signaling pathway is a signal transduction pathway important in regional and cellular differentiation during embryonic development.

Left-right determination factor 2 is a protein that in humans is encoded by the LEFTY2 gene.

Left-right determination factor 1 is a protein that in humans is encoded by the LEFTY1 gene.

Homeobox protein notochord (NOTO) is a transcription factor encoded by the gene notochord homeobox (NOTO) located on the short arm of chromosome 2 (2p13.2) in humans. An ortholog of NOTO is found in the house mouse, among other species, as the gene notochord homeobox (Noto) located on chromosome 6, which encodes the homologous transcription factor homeobox protein notochord (Noto).

Left-right asymmetry refers to differences in structure across the mediolateral plane in animals. This plane is defined with respect to the anteroposterior and dorsoventral axes and is perpendicular to both. Because the left-right plane is not strictly an axis, to create asymmetry, the left and right sides need to be patterned separately.

References

1 2 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. S2CID 20557143.
↑ 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. S2CID 5666974.
↑ 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. Bibcode:1996Natur.381..151M. doi:10.1038/381151a0. PMID 8610011. S2CID 4345275.
↑ 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.
1 2 Carlson, Bruce M. "Formation of Germ Layers and Early Derivatives." Human Embryology and Developmental Biology. Philadelphia, Pennsylvania: 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. Ernst Schering Research Foundation Workshop. 52 (52): 159–89. doi:10.1007/3-540-27147-3_8. ISBN 978-3-540-23089-2. PMID 15704472.
↑ Hashimoto M, Shinohara K, Wang J, Ikeuchi S, Yoshiba S, Meno C, Nonaka S, Takada S, Hatta K, Wynshaw-Boris A, Hamada H (February 2010). "Planar polarization of node cells determines the rotational axis of node cilia". Nature Cell Biology. 12 (2): 170–6. doi:10.1038/ncb2020. PMID 20098415.