QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 7 February 2007
doi: 10.1242/dev.000166

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, M. M. Search for Related Content PubMed PubMed Citation Articles by Shen, M. M. Social Bookmarking                         What's this?

Nodal signaling: developmental roles and regulation

Center for Advanced Biotechnology and Medicine and Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

View larger version (51K): [in this window] [in a new window]   Fig. 1. Schematic outline of the Nodal signaling pathway. (A) Nodal ligands are expressed as homodimeric proproteins, and can be cleaved extracellularly by the proprotein convertases Furin and Pace4. (B) Mature Nodal ligands, as well as Gdf1 and Gdf3, can bind to an EGF-CFC co-receptor in a complex with type I receptor (ALK4) and type II receptor (ActRII or ActRIIB) dimers. At least in some contexts, uncleaved Nodal proprotein can also signal through a similar receptor complex, although it is currently unknown whether such signaling is EGF-CFC dependent (Ben-Haim et al., 2006). (C) Cerberus and Lefty proteins are soluble antagonists that can interact with Nodal ligands; Lefty proteins can also interact with EGF-CFC co-receptors to inhibit their function. (D) Receptor activation leads to the phosphorylation of the type I receptor by the type II kinase, as well as phosphorylation of Smad2 (or Smad3). Activated Smad2 or Smad3 associates with Smad4 and translocates to the nucleus, whereas the receptor complex undergoes internalization into endosomes and can be targeted by Dpr2 for lysosomal degradation. (E) Within the nucleus, activated Smad2-Smad4 (or Smad3-Smad4) complexes interact with the winged-helix transcription factor FoxH1 or Mixer homeoproteins on target promoters, leading to transcriptional activation through interactions with ARC105 and the Mediator complex. Pathway activity can be inhibited by interaction of Drap1 with FoxH1 or by the Smad phosphatase Ppm1A, which promotes the nuclear export of Smad2 and possibly targets it for proteasomal degradation.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Reaction-diffusion mechanism for the generation of positional information. The generation of a stable Nodal signaling gradient (shown in blue) across a developmental field can result from a source of Nodal signals (at left) that undergo positive autoregulation and act at long-range (blue arrows). The expression of Lefty inhibitor (red) is also induced by the Nodal pathway, and has a greater range than Nodal signals. Cells in close proximity to the Nodal source thereby perceive high levels of signaling activity, whereas more distant cells perceive little or no signaling activity, as lateral inhibition by Lefty will prevail over a longer range. Such a regulatory mechanism for Nodal pathway activity may function during mesendoderm specification and left-right patterning. [Adapted from Branford and Yost (Branford and Yost, 2004).]

View larger version (31K): [in this window] [in a new window]   Fig. 3. Models of regulatory pathways for mesoderm induction. Depictions of embryos at pre-gastrulation stages. Domains of Nodal/Vg1 expression are indicated in blue; blue arrows indicate Nodal/Vg1 activity, orange arrows indicate Wnt/ß-catenin activity, and purple arrows correspond to the activity of other factors as noted. (A) In Xenopus (lateral view), zygotic Xnr transcripts (blue arrows) are activated by the maternally encoded VegT T-box transcription factor (purple arrow). Cortical rotation after fertilization leads to translocation of maternal dorsalizing signals and the stabilization of ß-catenin (orange arrow) on the dorsal side. The levels of Xnr as well as maternal Vg1 transcripts are higher dorsally (thicker blue arrows), and specify the dorsal-ventral patterning of the mesoderm in the marginal zone. (B) In zebrafish (lateral view), zygotic cyc and sqt transcripts (blue arrows) at the blastoderm margin are activated by an as yet unidentified signal(s) that emanates from the extraembryonic yolk syncytial layer. Graded Nodal signaling (thin and thick arrows) specifies the animal-vegetal patterning of mesoderm. (C) In the chick embryo (dorsal view), Vg1 (blue arrow) expressed at the posterior marginal zone cooperates with posteriorly-expressed Wnt8c (orange arrow) to induce streak formation in the adjacent epiblast. (D) In the mouse embryo (lateral view), Nodal proprotein (Nodal-Pp) expressed in the epiblast signals to the extraembryonic ectoderm, which activates expression of its proprotein convertases Furin and Pace4, as well as Bmp4. Production of the active mature Nodal ligand induces its positive autoregulatory loop (fast-acting; blue arrow), as well as a slower feedback loop (orange arrow) through Bmp4 and Wnt3; an additional feedback loop may take place through Cripto upregulation by Bmp4 and Wnt3 (Beck et al., 2002; Morkel et al., 2003).

View larger version (21K): [in this window] [in a new window]   Fig. 4. Anterior neural patterning by Nodal signaling and antagonism in the mouse embryo. Blue shading indicates regions expressing Nodal and/or Gdf3; red shading indicates regions expressing the Nodal antagonists Lefty1 and Cer1. Shortly after implantation, Nodal is expressed throughout the epiblast [5.25 days post-coitum (dpc)], and induces formation of the anterior visceral endoderm (AVE; red) at the distal end of the egg cylinder at 5.5 dpc; note that the initial appearance of the AVE is already slightly asymmetric, with a bias towards the prospective anterior side (Yamamoto et al., 2004). Nodal signaling is also required for the movement of the AVE (purple arrow) to the anterior side (5.75 dpc), where the expression of Nodal antagonists (Lefty1, Cer1) by the AVE is essential for the specification of anterior neural identity in the adjacent epiblast. Conversely, Nodal signaling is required for the generation of axial mesendoderm (orange) by the anterior primitive streak during gastrulation (7.5 dpc); in turn, the axial mesendoderm produces signaling factors (black arrows) that are essential for forebrain maintenance and ventral neural tube patterning.

View larger version (48K): [in this window] [in a new window]   Fig. 5. Sequential function of Nodal signaling in left-right patterning in the mouse embryo. (A) Following initial symmetry breaking around the node, possibly as a consequence of ciliary-based nodal flow, Nodal (green arrow) and/or Gdf1 signals become elevated on the left side of the node, and are antagonized by Cer2 (red). Nodal pathway activity then propagates to the left lateral plate mesoderm to activate left-sided Nodal expression, most likely through direct long-range action. (B) Nodal auto-regulates its own expression, which spreads through the left lateral plate mesoderm (green) through a positive-feedback loop. Lefty2 is induced through a negative-feedback loop, and subsequently downregulates Nodal expression (red bar). Axial midline expression of Lefty1 prevents the spread of left-sided Nodal signals, and suppresses ectopic Nodal activation on the right side.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

Twitter