Nodal signaling pathway

[1] The Nodal family of proteins, a subset of the transforming growth factor beta (TGFβ) superfamily, is responsible for mesoendoderm induction, patterning of the nervous system, and determination of dorsal- ventral axis in vertebrate embryos.

The P-Smad2/Smad4 complex translocates into the nucleus to interact with transcription factors such as FoxH1, p53 and Mixer (Xenopus mix-like endodermal regulator).

[2][3] This balance of activation and inhibition of the signal is necessary to achieve the precise location, concentration and duration of downstream target genes that have an important role early in development.

This article will summarize the role of some of the components that participate positively and negatively in regulation the signaling pathway.

DAN proteins, such as Cerberus and Coco in Xenopus and Cerberus-like in mouse, also act as antagonists of Nodal signaling.

[11] EGF-CFC proteins are membrane bound extracellular factors that serve as essential cofactor in Nodal signaling and in vertebrate development as a whole.

This family of cofactors includes One-eyed Pinhead (oep) in Zebrafish, FRL1 in Xenopus, and Cripto and Criptic in mouse and human.

This evidence coupled with the data that overexpression of oep shows no phenotype corroborates the role of EGF-CFC as an essential cofactor in Nodal signaling.

[12] In mouse, frog and fish, Dapper2, is a negative regulator of mesoderm formation acting through the down-regulation of the Wnt and TGFβ / nodal signaling pathways.

In the mouse embryo, dpr2 mRNA is located across all the embryo 7.5 days post conception (dpc) however its location changes at 8.5-dpc where it is observed at the prospective somites and by 10-dpc, neural tube, otic vesicle and gut; because Dapper2 and Nodal are expressed in the same region, this suggests that Dapper antagonizes mesoderm induction signals derived from Nodal.

It has important roles in controlling mesoderm and endoderm specification, and it does it by regulating the protein expression levels of some Nodal signaling components.

[22] Multiple studies have established that Nodal signal is required for the induction of most mesodermal and endodermal cell types and Squint/Cyclops knockouts in Zebrafish do not develop notochord, heart, kidneys or even blood.

With the addition of antagonists and variable range of different nodals, a map of cell fates including both mesoderm and endoderm can be drawn for the embryo.

These genetic studies led to identification of mutations in components in the nodal signaling pathway such as ActRIIB, Criptic, and FoxH1 in mouse.

Xenopus nodal related 3, (Xnr3) a divergent member of the TGFβ superfamily, induces the expression of the protein, Xbra.

This signaling in conjuncture with other nodals, noggin, chordin, follistatin and others results in the final patterning of vertebrate central nervous system.

Overview of Nodal signaling pathway. Nodal and its repressor Lefty are both expressed in response to Nodal signaling. The protein expression levels are affected due to the activity of the miR-430 super-family. Once the protein is translated, it has to be processed in the extracellular space by Convertases (Furin and PACE4). Mature Nodal binds to the Activin receptors I and II and the co-receptor Cripto/Criptic and phosphorilates Smad2 /3. These Smads form a complex with Smad4 and enter into the nucleus and with the help of p53, Mixer or FoxH1 activate the transcription of genes involved in mesoderm and endoderm induction. Ectodermin, PPM1A, XFDR and Tgf1 negative regulate the pathway by competing with Smad components or transcription factors. The interaction of Nodal with BMPs (BMP3, BMP7), Lefty or with Cerberus in the outside of the cells affects its capability to bind to the receptors and reactivate the signal.