Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo

Abstract

Genetic and biochemical data have identified Smad4 as a key intracellular effector of the transforming growth factor β (TGFβ superfamily of secreted ligands. In mouse, Smad4-null embryos do not gastrulate, a phenotype consistent with loss of other TGFβ-related signaling components. Chimeric analysis reveals a primary requirement for Smad4in the extra-embryonic lineages; however, within the embryo proper,characterization of the specific roles of Smad4 during gastrulation and lineage specification remains limited. We have employed a Smad4conditional allele to specifically inactivate the Smad4 gene in the early mouse epiblast. Loss of Smad4 in this tissue results in a profound failure to pattern derivatives of the anterior primitive streak, such as prechordal plate, node, notochord and definitive endoderm. In contrast to these focal defects, many well-characterized TGFβ- and Bmp-regulated processes involved in mesoderm formation and patterning are surprisingly unaffected. Mutant embryos form abundant extra-embryonic mesoderm, including allantois, a rudimentary heart and middle primitive streak derivatives such as somites and lateral plate mesoderm. Thus, loss of Smad4 in the epiblast results not in global developmental abnormalities but instead in restricted patterning defects. These results suggest that Smad4 potentiates a subset of TGFβ-related signals during early embryonic development, but is dispensable for others.

Koreans admit disguising stem-cell lines

“…In addition to the expression of germ cell markers, we noticed a significant difference in the expression of genes in the TGFβ pathway, such as GDF3 ( Figure 6C), TGFBI, CDKN1A, IGFBP7, IGFBP3, NODAL, CER1 and BMP2 ( Figure 6E). This is consistent with the postulated role of this pathway in germ cell differentiation [22,23] and suggests that TGFβ pathway cannot be reliably tested using NTera2 as a model for hESC.…”

Function of the Two Xenopus Smad4s in Early Frog Development

“…Currently, it is unclear whether all aspects of early TGF␤ signals are affected in Smad4 knockdown frog embryos. In mouse, specific elimination of Smad4 in epiblast cells leads to defects in only a subset of TGF␤-and BMP-regulated processes (10,11). In Drosophila, the Smad4 homolog Medea also potentiates most but not all Dpp-dependent responses (13).…”

“…Thus chimeric mouse embryos, containing Smad4-null epiblast cells, form patterned mesoderm that gives rise to the heart, trunk somites, and lateral plate mesoderm, a phenotype different from that expected if both nodal and BMP signals are impaired (10). Murine fibroblast cells deficient in Smad4 still respond to TGF␤/activin-mediated growth inhibition and induction of extracellular matrix genes (11).…”

Blimp1 and the Emergence of the Germ Line during Development in the Mouse

“…Furthermore, molecules belonging to the Bone morphogenetic protein (Bmp) signaling pathway were shown to be necessary for PGC specification in embryos by gene knock-out studies. [13][14][15][16][17][18][19][20] However, many of these mutant embryos also showed abnormalities of the allantois, 13,[15][16][17]20 indicating that Bmp signaling from the extraembryonic ectoderm is important for priming the proximal epiblast cells to make them competent not only for the specification of PGCs, but also for development of the extraembryonic mesodermal tissues. Thus, it would seem that additional factors are probably necessary that play an essential role during the specification of PGCs exclusively.…”