Disease relevance of Smad5

• The Smad5 IRES was 4-8-fold more active than the poliovirus IRES in C2C12 cells, which have osteoblastic differentiation ability, but was 5-10-fold less active than the poliovirus IRES in 293T cells [1].
• Our analysis shows that BMP4/Madh5-dependent signaling, regulated by hypoxia, initiates the differentiation and expansion of erythroid progenitors in the spleen [2].

High impact information on Smad5

• RUNX2 functions synergistically with Smad1 and Smad5 to regulate bone-specific genes when BMP induces osteogenesis [3].
• Smad5 is dispensable for adult murine hematopoiesis [4].
• Here, we evaluate the role of Smad5 in the regulation of hematopoietic stem cell (HSC) fate decisions in adult mice by using an inducible MxCre-mediated conditional knockout model [4].
• Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin(-)Sca-1(+)c-Kit(+) (LSK) cells in Smad5(-)(/)(-) BM [4].
• BMP4 and Madh5 regulate the erythroid response to acute anemia [2].

Biological context of Smad5

• Smad5 mutant embryos had enlarged blood vessels surrounded by decreased numbers of vascular smooth muscle cells, suffered massive apoptosis of mesenchymal cells, and were unable to direct angiogenesis in vitro [5].
• We showed that Smad5 was expressed predominantly in mesenchyme and somites during embryogenesis, and in many tissues of the adult [5].
• Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins [6].
• BMP exert their biologic effects via binding to two types of serine/threonine kinase BMP receptors, activation of which leads to phosphorylation and translocation into the nucleus of intracellular signaling molecules, including Smad1, Smad5, and Smad8 ("canonical" BMP signaling pathway) [7].
• Injection of rBMP4 in the exocoelom of wild-type embryos can induce thickening of amnion, mimicking the early amnion phenotype in Smad5 mutants [8].

Anatomical context of Smad5

• Its receptor Alk3 and the R-Smad Smad5 are specifically expressed both in proliferating primordial germ cells and in postnatal spermatogonia [9].
• Here we show that the signaling mediators Smad1-Smad5 are expressed at all stages of mammary gland development [10].
• On the other hand, Smad1 and Smad5 decreased myogenin-CAT activity but did not induce ALP activity in MyoD-transfected NIH3T3 fibroblasts [11].
• Previous research has shown that Smad1 is important in the formation of the allantois, while Smad5 has been shown to be critical in the process of angiogenesis [12].
• We show that defects in amnion and allantois can already be detected at embryonic day (E) 7.5 in Smad5 mutant mice [8].

Other interactions of Smad5

• Core-binding factor alpha 1 (Cbfa1) induces osteoblastic differentiation of C2C12 cells without interactions with Smad1 and Smad5 [13].
• The function of NRAGE is independent of Smad signaling, but the introduction of a dominant-negative Smad5 also rescues neural progenitor apoptosis, suggesting that both canonical and noncanonical pathways can converge and regulate BMP-mediated apoptosis [14].
• Our previous studies have shown that SMAD5, an important intracellular mediator of transforming growth factor beta (TGF-beta) family, is required for normal development of the cardiovascular system in vivo [15].
• These results suggest that the Smad5-mediated TGF-beta signals may protect cardiomyocytes from apoptosis by maintaining the integrity of the mitochondria, probably through suppression of p53 mediated pathways [15].
• Smad5 is thought to relay signals of the bone morphogenetic protein pathway [1].

Analytical, diagnostic and therapeutic context of Smad5

• By electron microscopy, abnormal swollen mitochondria were observed in cardiomyocytes both from Smad5-deficient embryos and from ES-differentiated cells [15].

References