Long-range action of Nodal requires interaction with GDF1

GDF1 (growth/differentiation factor 1), a Vg1-related member of the transforming growth factor-β superfamily, is required for left–right patterning in the mouse, but the precise function of GDF1 has remained largely unknown. In contrast to previous observations, we now show that GDF1 itself is not an effective ligand but rather functions as a coligand for Nodal. GDF1 directly interacts with Nodal and thereby greatly increases its specific activity. Gdf1 expression in the node was found necessary and sufficient for initiation of asymmetric Nodal expression in the lateral plate of mouse embryos. Coexpression of GDF1 with Nodal in frog embryos increased the range of the Nodal signal. Introduction of Nodal alone into the lateral plate of Gdf1 knockout mouse embryos did not induce Lefty1 expression at the midline, whereas introduction of both Nodal and GDF1 did, showing that GDF1 is required for long-range Nodal signaling from the lateral plate to the midline. These results suggest that GDF1 regulates the activity and signaling range of Nodal through direct interaction

Aberrant differentiation of second heart field mesoderm prefigures cellular defects in the outflow tract in response to loss of FGF8

International audienceDevelopment of the outflow tract of the heart requires specification, proliferation and deployment of a progenitor cell population from the second heart field to generate the myocardium at the arterial pole of the heart. Disruption of these processes leads to lethal defects in rotation and septation of the outflow tract. We previously showed that Fibroblast Growth Factor 8 (FGF8) directs a signaling cascade in the second heart field that regulates critical aspects of OFT morphogenesis. Here we show that in addition to the survival and proliferation cues previously described, FGF8 provides instructive and patterning information to OFT myocardial cells and their progenitors that prevents their aberrant differentiation along a working myocardial program

The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse

FoxH1 (FAST) is a transcription factor that mediates signaling by transforming growth factor–β, Activin, and Nodal. The role of FoxH1 in development has now been investigated by the generation and analysis of FoxH1-deficient (FoxH1(−/−)) mice. The FoxH1(−/−) embryos showed various patterning defects that recapitulate most of the defects induced by the loss of Nodal signaling. A substantial proportion of FoxH1(−/−) embryos failed to orient the anterior-posterior (A-P) axis correctly, as do mice lacking Cripto, a coreceptor for Nodal. In less severely affected FoxH1(−/−) embryos, A-P polarity was established, but the primitive streak failed to elongate, resulting in the lack of a definitive node and its derivatives. Heterozygosity for nodal renders the FoxH1(−/−) phenotype more severe, indicative of a genetic interaction between FoxH1 and nodal. The expression of FoxH1 in the primitive endoderm rescued the A-P patterning defects, but not the midline defects, of FoxH1(−/−) mice. These results indicate that a Nodal-FoxH1 signaling pathway plays a central role in A-P patterning and node formation in the mouse

A glycan-based approach to therapeutic angiogenesis.

Angiogenesis, the sprouting of new blood vessels from existing vasculature, involves multiple complex biological processes, and it is an essential step for hemostasis, tissue healing and regeneration. Angiogenesis stimulants can ameliorate human disease conditions including limb ischemia, chronic wounds, heart disease, and stroke. The current strategies to improve the bioavailability of pro-angiogenic growth factors, including VEGF and FGF2, have remained largely unsuccessful. This study demonstrates that small molecules, termed click-xylosides, can promote angiogenesis in the in vitro matrigel tube formation assay and the ex ovo chick chorioallantoic membrane assay, depending on their aglycone moieties. Xyloside treatment enhances network connectivity and cell survivability, thereby, maintaining the network structures on matrigel culture for an extended period of time. These effects were achieved via the secreted xyloside-primed glycosaminoglycans (GAG) chains that in part, act through an ERK1/2 mediated signaling pathway. Through the remodeling of GAGs in the extracellular matrix of endothelial cells, the glycan approach, involving xylosides, offers great potential to effectively promote therapeutic angiogenesis