Lefty (protein)
Encyclopedia
Lefty are protein
s 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.
) 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 vertibrates 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.
pathway. 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
. (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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s 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
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
. Mutations of the genes encoding these proteins have been associated with left-right axis malformations, particularly in the heart and lungs.
History
Lefty, a divergent member of the transforming growth factor-β (TGF betaTGF beta
Transforming growth factor beta is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, and Loeys–Dietz syndrome....
) superfamily of proteins, was originally discovered in the Hamada lab at the Osaka University
Osaka University
, or , is a major national university located in Osaka, Japan. It is the sixth oldest university in Japan as the Osaka Prefectural Medical College, and formerly one of the Imperial Universities of Japan...
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
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
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 vertibrates 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.
Function
Lefty proteins function as an antagonist of the Nodal SignalingNodal signaling
Nodal signaling is a signal transduction pathway that is important in pattern formation and differentiation during embryo development.The nodal family of proteins, a subset of the transforming growth factor beta superfamily, is responsible for mesoendoderm induction, patterning of the nervous...
pathway. As NODAL
NODAL
Nodal is a protein that in humans is encoded by the NODAL gene. It is a member of the TGF beta superfamily. Like many other members of this superfamily, it is involved in cell differentiation...
protein diffuse through an embryo, it triggers Nodal Signaling
Nodal signaling
Nodal signaling is a signal transduction pathway that is important in pattern formation and differentiation during embryo development.The nodal family of proteins, a subset of the transforming growth factor beta superfamily, is responsible for mesoendoderm induction, patterning of the nervous...
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
NODAL
Nodal is a protein that in humans is encoded by the NODAL gene. It is a member of the TGF beta superfamily. Like many other members of this superfamily, it is involved in cell differentiation...
/ Activin-like receptor complex. This will effectually block Nodal Signaling
Nodal signaling
Nodal signaling is a signal transduction pathway that is important in pattern formation and differentiation during embryo development.The nodal family of proteins, a subset of the transforming growth factor beta superfamily, is responsible for mesoendoderm induction, patterning of the nervous...
. (See Nodal Signaling
Nodal signaling
Nodal signaling is a signal transduction pathway that is important in pattern formation and differentiation during embryo development.The nodal family of proteins, a subset of the transforming growth factor beta superfamily, is responsible for mesoendoderm induction, patterning of the nervous...
or TGF beta signaling pathway
TGF beta signaling pathway
The Transforming growth factor beta signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular...
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
Situs inversus
Situs inversus is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement is known as situs solitus...
), 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
NODAL
Nodal is a protein that in humans is encoded by the NODAL gene. It is a member of the TGF beta superfamily. Like many other members of this superfamily, it is involved in cell differentiation...
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
Nodal signaling
Nodal signaling is a signal transduction pathway that is important in pattern formation and differentiation during embryo development.The nodal family of proteins, a subset of the transforming growth factor beta superfamily, is responsible for mesoendoderm induction, patterning of the nervous...
results in the patterning of the embryo and left-right asymmetry.