Studying TGF-β superfamily signaling by knockouts and knockins

Chang, Hua; Lau, Anthony L.; Matzuk, Martin M.

doi:10.1016/s0303-7207(01)00513-5

Cited by 72 publications

(42 citation statements)

References 71 publications

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“…Here, we found that Smad2 plays an essential role in expression of several mesendodermal lineage markers (e.g., Gsc, Lhx1 and Sox17). This is also in agreement with the roles of Activin/Nodal signaling in early embryo development [14,15]. Notably, Smad2 knockout mice are embryonic lethal due to severe defects in germ layer specification, whereas Smad3-deficient mice are viable and fertile but display aberrant phenotypes in immunity (reviewed in [13]).…”

Section: Discussionsupporting

confidence: 81%

“…The two groups of TGF-β superfamily members employ different sets of R-Smads to transduce their signals: TGF-β/Activin/Nodal mainly activate Smad2 and Smad3, whereas BMP/GDF generally utilize Smad1, Smad5 and Smad8. Genetic and biochemical studies have well documented that Smad2, but not Smad3, plays a critical role in mediating Activin/Nodal signaling to regulate mouse embryo development [13][14][15], indicating the potential significance of Smad2 in ES cell fate determination.…”

Section: Introductionmentioning

confidence: 99%

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Smad2 mediates Activin/Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells

et al. 2010

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Although Activin/Nodal signaling regulates pluripotency of human embryonic stem (ES) cells, how this signaling acts in mouse ES cells remains largely unclear. To investigate this, we confirmed that mouse ES cells possess active Smad2-mediated Activin/Nodal signaling and found that Smad2-mediated Activin/Nodal signaling is dispensable for self-renewal maintenance but is required for proper differentiation toward the mesendoderm lineage. To gain insights into the underlying mechanisms, Smad2-associated genes were identified by genome-wide chromatin immunoprecipitation-chip analysis. The results showed that there is a transcriptional correlation between Smad2 binding and Activin/Nodal signaling modulation, and that the development-related genes were enriched among the Smad2-bound targets. We further identified Tapbp as a key player in mesendoderm differentiation of mouse ES cells acting downstream of the Activin/Nodal-Smad2 pathway. Taken together, our findings suggest that Smad2-mediated Activin/Nodal signaling orchestrates mesendoderm lineage commitment of mouse ES cells through direct modulation of corresponding developmental regulator expression.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Smad2 mediates Activin/Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells

et al. 2010

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“…As a result, one potential role for activin A could be as a negative feedback inhibitor of IL-1 and IL-6 production and action within both the seminiferous tubules and interstitial tissue. Although there is no doubt that spermatogenesis can persist in mice deficient in IL-1, activin A, or even FSH production and/or signalling, albeit at a reduced level in some cases (Cohen & Pollard 1998, Chang et al 2001, Sairam & Krishnamurthy 2001, the presence of these hormones/ cytokines and the intersection of their signalling pathways in this tissue must have physiological consequences. In this regard, it is interesting to note that there is cyclical regulation of both IL-1 and A -subunit mRNA across the cycle of seminiferous epithelium , Kaipia et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of activin A and inhibin B by interleukin-1 (IL-1) and follicle-stimulating hormone (FSH) in rat Sertoli cells in vitro

Okuma

Saito

O’Connor

et al. 2005

Journal of Endocrinology

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In several biological systems, the inhibin A homodimer activin A is stimulated by, and in turn, inhibits the action of interleukin (IL)-1 (both IL-1 and IL-1 ) and IL-6. The possibility that a similar regulatory relationship operates within the testis was investigated. Sertoli cells from immature (20-day-old) rats were cultured with human IL-1 or IL-1 , human IL-6 and/or ovine FSH or dibutyryl cAMP. Activin A and the inhibin dimers, inhibin A and inhibin B, were measured by specific ELISA. Immunoreactive inhibin (ir-inhibin) was measured by RIA. Activin/inhibin subunit mRNA expression was measured by quantitative real-time PCR. Both IL-1 isoforms, but not IL-6, stimulated activin A secretion through increased synthesis of A -subunit mRNA. IL-1 also stimulated activin A secretion by testicular peritubular cells. In contrast to the effect on activin A, IL-1 suppressed inhibin B -subunit and, to a lesser extent, -subunit mRNA expression, thereby reducing basal and FSHstimulated inhibin B secretion by the Sertoli cells. Conversely, FSH inhibited basal activin A secretion and antagonised the stimulatory effects of IL-1. Dibutyryl cAMP partially inhibited the action of IL-1 on activin A secretion, but had no significant effect on basal activin A secretion. Secretion of inhibin A was low in all treatment groups. These data demonstrate that IL-1 and FSH/cAMP exert a reciprocal regulation of activin A and inhibin B synthesis and release by the Sertoli cell, and suggest a role for activin A as a potential feedback regulator of IL-1 and IL-6 activity in the testis during normal spermatogenesis and in inflammation.

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“…Thus, our data defines a novel function of IKK-1 as an essential mediator of TGF-b1-induced NF-kB activation. Since IKK-1 null mice display morphogenic defects (Hu et al, 1999;Takeda et al, 1999), it will be crucial to determine whether other TGF-b family members, which have been implicated in the regulation of vertebrate development (Chang et al, 2001), signal through IKK-1. In addition, we have identified TAK1 as an upstream mediator of IKK activation.…”

Section: Discussionmentioning

confidence: 99%

Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

et al. 2003

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Studying TGF-β superfamily signaling by knockouts and knockins

Cited by 72 publications

References 71 publications

Smad2 mediates Activin/Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells

Smad2 mediates Activin/Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells

Reciprocal regulation of activin A and inhibin B by interleukin-1 (IL-1) and follicle-stimulating hormone (FSH) in rat Sertoli cells in vitro

Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

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