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PMID:17936261

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Citation

Andersson, O, Bertolino, P and Ibáñez, CF (2007) Distinct and cooperative roles of mammalian Vg1 homologs GDF1 and GDF3 during early embryonic development. Dev. Biol. 311:500-11

Abstract

Vg1, a member of the TGF-beta superfamily of ligands, has been implicated in the induction of mesoderm, formation of primitive streak, and left-right patterning in Xenopus and chick embryos. In mice, GDF1 and GDF3 - two TGF-beta superfamily ligands that share high sequence identity with Vg1 - have been shown to independently mimic distinct aspects of Vg1's functions. However, the extent to which the developmental processes controlled by GDF1 and GDF3 and the underlying signaling mechanisms are evolutionarily conserved remains unclear. Here we show that phylogenetic and genomic analyses indicate that Gdf1 is the true Vg1 ortholog in mammals. In addition, and similar to GDF1, we find that GDF3 signaling can be mediated by the type I receptor ALK4, type II receptors ActRIIA and ActRIIB, and the co-receptor Cripto to activate Smad-dependent reporter genes. When expressed in heterologous cells, the native forms of either GDF1 or GDF3 were incapable of inducing downstream signaling. This could be circumvented by using chimeric constructs carrying heterologous prodomains, or by co-expression with the Furin pro-protein convertase, indicating poor processing of the native GDF1 and GDF3 precursors. Unexpectedly, co-expression with Nodal - another TGF-beta superfamily ligand involved in mesoderm formation - could also expose the activities of native GDF1 and GDF3, suggesting a potentially novel mode of cooperation between these ligands. Functional complementarity between GDF1 and GDF3 during embryonic development was investigated by analyzing genetic interactions between their corresponding genes. This analysis showed that Gdf1(-/-);Gdf3(-/-) compound mutants are more severely affected than either Gdf1(-/-) or Gdf3(-/-) single mutants, with defects in the formation of anterior visceral endoderm and mesoderm that recapitulate Vg1 loss of function, suggesting that GDF1 and GDF3 together represent the functional mammalian homologs of Vg1.

Links

PubMed Online version:10.1016/j.ydbio.2007.08.060

Keywords

Activin Receptors, Type I/genetics; Activin Receptors, Type I/metabolism; Activin Receptors, Type II/genetics; Activin Receptors, Type II/metabolism; Animals; Body Patterning; Cell Line; Chickens; Embryo, Mammalian/anatomy & histology; Embryo, Mammalian/physiology; Epidermal Growth Factor/genetics; Epidermal Growth Factor/metabolism; Growth Differentiation Factor 1; Growth Differentiation Factor 3; Humans; In Situ Hybridization; Intercellular Signaling Peptides and Proteins/classification; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Mesoderm/cytology; Mesoderm/physiology; Mice; Mice, Knockout; Morphogenesis; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Nodal Protein; Phylogeny; Protein Precursors/genetics; Protein Precursors/metabolism; Signal Transduction/physiology; Transforming Growth Factor beta/classification; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism; Xenopus; Xenopus Proteins/classification; Xenopus Proteins/genetics; Xenopus Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GDF1

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2181719

P

Seeded From UniProt

complete

MOUSE:GDF1

acts_upstream_of_or_within

GO:0007498: mesoderm development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95686

P

Seeded From UniProt

complete

MOUSE:GDF1

acts_upstream_of_or_within

GO:0007492: endoderm development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95686

P

Seeded From UniProt

complete

MOUSE:GDF1

acts_upstream_of_or_within

GO:0007165: signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2181719

P

Seeded From UniProt

complete

MOUSE:GDF1

acts_upstream_of_or_within

GO:0007165: signal transduction

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95686

P

Seeded From UniProt

complete

MOUSE:AVR2A

acts_upstream_of_or_within

GO:0009966: regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AVR2B

acts_upstream_of_or_within

GO:0009966: regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NODAL

acts_upstream_of_or_within

GO:0009966: regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TDGF1

acts_upstream_of_or_within

GO:0009966: regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GDF3

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3764814

P

Seeded From UniProt

complete

MOUSE:GDF3

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95683

P

Seeded From UniProt

complete

MOUSE:GDF3

acts_upstream_of_or_within

GO:0007498: mesoderm development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95683

P

Seeded From UniProt

complete

MOUSE:GDF3

acts_upstream_of_or_within

GO:0007492: endoderm development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95683

P

Seeded From UniProt

complete

MOUSE:GDF3

acts_upstream_of_or_within

GO:0007165: signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3764814

P

Seeded From UniProt

complete

MOUSE:ACV1B

acts_upstream_of_or_within

GO:0009966: regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FURIN

acts_upstream_of_or_within

GO:0009966: regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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