Transforming Growth Factor-β Stimulates Mouse Blastocyst Outgrowth through a Mechanism Involving Parathyroid Hormone-Related Protein1

Nowak, Romana A.; Haimovici, Florina; Biggers, John D.; Erbach, Gregory T.

doi:10.1095/biolreprod60.1.85

Cited by 35 publications

(34 citation statements)

References 52 publications

(67 reference statements)

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“…Co-expression of inhibitory Smad 7 indicates the potential for tight regulation of activin/ TGFb action during cleavage and blastocyst development (Zwijsen et al 2000). Exogenous TGFb facilitates embryonic development in vitro, promoting blastocyst proliferation and development and increasing blastocyst cell number (Paria & Dey 1990, Lim et al 1993, Nowak et al 1999 (Fig. 1).…”

Section: Regulation Of Early Embryo Developmentmentioning

confidence: 99%

TGF-β superfamily expression and actions in the endometrium and placenta

et al. 2006

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Transforming growth factor b (TGFb) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFb superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFbs and activin b subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFbs, nodal and bone morphogenetic proteins (BMPs) in promoting pre-and post-implantation embryo development. TGFb superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFb and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFb superfamily members participate in modulating the extent of decidual invasion. Activins and TGFbs have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down's syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

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Section: Regulation Of Early Embryo Developmentmentioning

confidence: 99%

TGF-β superfamily expression and actions in the endometrium and placenta

et al. 2006

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“…2B). After culturing for 3-4 days, spherical blastocysts became flattened on the culture dish and formed a multicomponent structure in which the inner cell mass grew as a round shape on top of the extra-embryonic trophoblast giant cells (32). In these cultures heterozygous TopBP1 ϩ/⌬ and wild-type embryonic cells normally developed into inner cell mass and trophoblast giant cells.…”

Section: Mefs Suggests That the Topbp1mentioning

confidence: 99%

TopBP1 Deficiency Causes an Early Embryonic Lethality and Induces Cellular Senescence in Primary Cells

Jeon

Lee

et al. 2011

Journal of Biological Chemistry

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TopBP1 plays important roles in chromosome replication, DNA damage response, and other cellular regulatory functions in vertebrates. Although the roles of TopBP1 have been studied mostly in cancer cell lines, its physiological function remains unclear in mice and untransformed cells. We generated conditional knock-out mice in which exons 5 and 6 of the TopBP1 gene are flanked by loxP sequences. Although TopBP1-deficient embryos developed to the blastocyst stage, no homozygous mutant embryos were recovered at E8.5 or beyond, and completely resorbed embryos were frequent at E7.5, indicating that mutant embryos tend to die at the periimplantation stage. This finding indicated that TopBP1 is essential for cell proliferation during early embryogenesis. Ablation of TopBP1 in TopBP1 flox/flox mouse embryonic fibroblasts and 3T3 cells using Cre recombinase-expressing retrovirus arrests cell cycle progression at the G 1 , S, and G 2 /M phases. The TopBP1-ablated mouse cells exhibit phosphorylation of H2AX and Chk2, indicating that the cells contain DNA breaks. The TopBP1-ablated mouse cells enter cellular senescence. Although RNA interference-mediated knockdown of TopBP1 induced cellular senescence in human primary cells, it induced apoptosis in cancer cells. Therefore, TopBP1 deficiency in untransformed mouse and human primary cells induces cellular senescence rather than apoptosis. These results indicate that TopBP1 is essential for cell proliferation and maintenance of chromosomal integrity.TopBP1 5 is conserved in eukaryotes and contains repeats of BRCA1 carboxyl-terminal motifs, which are found in proteins involved in DNA repair and regulation of cell cycle checkpoints (1-6). Recent findings indicate that TopBP1 participates in the loading of Cdc45 for the assembly of the preinitiation complex that is necessary for chromosomal DNA replication (7-11). Knockdown of TopBP1 in human cancer cells showed that TopBP1 is necessary for the activation of cyclin E/CDK2 and Cdc7/Dbf4 kinases as well as the loading of DNA polymerase onto chromatin (12). In response to replication fork stalling or DNA damage, TopBP1 functions as an activator of the ATR⅐ATRIP complex by binding to Rad9 of the Rad9⅐Hus1⅐Rad1 complex (13,14). The activated ATR phosphorylates Chk1, Nbs1, Smc1, and H2AX (15-18). TopBP1 also mediates ATR-mediated Chk1 activation by facilitating the interaction of claspin and Chk1 (19,20). Furthermore, association of TopBP1 with NBS1 is involved in double-stranded DNA break-induced homologous recombination repair (21). Therefore, TopBP1 plays crucial roles in the maintenance of genomic integrity.TopBP1 regulates gene expression. Binding of TopBP1 to E2F1 represses E2F1 proapoptotic activity by recruiting the Brg1⅐Brm chromatin remodeling complex (22). TopBP1 also binds to the DNA binding domain of p53 and inhibits the promoter binding activity of this protein (23). Therefore, TopBP1 depletion derepresses the proapoptotic activity of p53 and E2F1 and induces cellular apoptosis. In addition, TopBP1 represses Miz-1 express...

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“…There are indications however that TGF-␤ signaling interferes with extracellular matrix deposition in trophectoderm cells as overexpression of T␤RII in preimplantation embryos was shown to upregulate laminin deposition (Mummery and van den Eijnden-van Raaij, 1999). By contrast, Nowak et al (1999) found a marked increase in the area of trophoblast outgrowths exposed to TGF-␤1. Interestingly, this growth stimulatory effect could be inhibited by simultaneous addition of parathyroid hormone-related peptide (PTHrP) neutralizing antibodies.…”

Section: Tgf-␤ In Trophectodermmentioning

confidence: 74%

“…Interestingly, this growth stimulatory effect could be inhibited by simultaneous addition of parathyroid hormone-related peptide (PTHrP) neutralizing antibodies. Since PTHrP can increase trophoblast outgrowth, these results suggest that in trophoblasts TGF-␤1-induced outgrowth acts by increasing the PTHrP production by the blastocyst (Nowak et al, 1999).…”

Section: Tgf-␤ In Trophectodermmentioning

confidence: 77%