Ectodermal Factor Restricts Mesoderm Differentiation by Inhibiting p53

Sasai, Noriaki; Yakura, Rieko; Kamiya, Daisuke; Nakazawa, Yoko; Sasai, Yoshiki

doi:10.1016/j.cell.2008.03.035

Cited by 39 publications

(40 citation statements)

References 51 publications

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“…In Xenopus, in which p63 and p73 are not expressed during development (45), inhibition of p53 blocks terminal differentiation (46). Furthermore, regulated expression of a p53 interactor, XFDL156, prevents mesoderm specification in the presumptive ectoderm by inhibiting p53 (33). These reports indicate a role for p53 regulation in differentiation processes during amphibian development and are supportive of our findings.…”

Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modsupporting

confidence: 86%

“…These defects are not caused by induction of apoptosis, indicating that p53 down-regulation is not required for the prevention of programmed cell death but instead plays a different role during blastema formation. Physiological down-regulation of p53 has been previously reported in human embryonic stem cells exposed to hypoxia, where it leads to a state of "enhanced stemness" (32), and during development in Xenopus, where it is required for maintaining ectodermal cells in a pluripotent state (33). Furthermore, inhibition of p53 activity by AurK is crucial for the maintenance of both embryonic and induced pluripotency (34), and during induced pluripotent stem cell induction the reprogramming process itself leads to p53 down-regulation (15).…”

Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modmentioning

confidence: 91%

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Regulation of p53 is critical for vertebrate limb regeneration

Yun

Gates

Brockes

2013

Proc. Natl. Acad. Sci. U.S.A.

108

101

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Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures. Despite their importance, the mechanisms underlying the regulation of the differentiated state during regeneration remain unclear. Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its upregulation is necessary for the redifferentiation phase. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. Our results suggest that the regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration. myogenesis | chondrogenesis | p73 | carcinogenesis U nlike mammals, which exhibit limited regenerative abilities, the urodele amphibians-or salamanders-are capable of regenerating an extraordinary range of body structures, including ocular tissues, tail, sections of the heart, parts of the nervous system, and entire limbs (1). In salamanders, such as the newt and axolotl, limb regeneration depends on the formation of a blastema, a mound of progenitor cells of restricted potential that arises after amputation (2-4). Following a period of proliferation, blastema cells redifferentiate and restore the structures of the limb.Extensive evidence indicates that limb regeneration depends on reprogramming of cells in mature limb tissues. Upon amputation, muscle, cartilage, and connective tissue cells underneath the injury site lose their differentiated characteristics and reenter the cell cycle to give rise to the blastema (5-8). This mechanism has also been observed during zebrafish heart and fin regeneration (9, 10). In contrast, reversals of the differentiated state are rarely observed in mammalian tissues, which led to the suggestion that inability to undergo dedifferentiation could contribute to the failure of regeneration in mammals (11). Despite their significance, the mechanisms underlying regulation of the differentiated state during vertebrate regeneration remain poorly understood.Recently, the tumor suppressor p53, whose best-characterized functions are in the maintenance of genome stability (12), has been implicated in the suppression of artificial cell reprogramming to pluripotency (13-17) and the promotion of differentiation pathways in mammals (18). In addition, it has been observed that inhibiting p...

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Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modsupporting

confidence: 86%

Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modmentioning

confidence: 91%

Regulation of p53 is critical for vertebrate limb regeneration

Yun

Gates

Brockes

2013

Proc. Natl. Acad. Sci. U.S.A.

108

101

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“…This interaction leads to the transcriptional induction of mesoderm-defining genes, such as the transcription factors Snail, Xbra (brachyury) and Mix.2. Conversely, during Xenopus ectoderm specification, p53 is inhibited by the zinc-finger protein XFDL156 (Sasai et al, 2008). This mechanism is essential for preventing the aberrant activation of nodal signaling in the ectoderm, the developmental fate of which depends primarily on the activity of BMP pathways.…”

Section: Regulatory Mechanisms Of Smad Transcriptional Co-factorsmentioning

confidence: 99%

The regulation of TGFβ signal transduction

2009

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Transforming growth factor  (TGF) pathways are implicated in metazoan development, adult homeostasis and disease. TGF ligands signal via receptor serine/threonine kinases that phosphorylate, and activate, intracellular Smad effectors as well as other signaling proteins. Oligomeric Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF family members. Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGF signal transduction in metazoans and emphasize events crucial for embryonic development. IntroductionThe human transforming growth factor  (TGF) family consists of 33 members, most of which encode dimeric, secreted polypeptides that control developmental processes, ranging from gastrulation and body axis asymmetry to organ-specific morphogenesis and adult tissue homeostasis (reviewed by Derynck and Miyazono, 2008). In addition to TGFs, this family includes the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins and nodal. The TGF family is conserved throughout metazoan evolution. At the cellular level, TGF family members regulate cell growth, differentiation, adhesion, migration and death, in a developmental context-dependent and cell type-specific manner. For example, TGF more often inhibits, but sometimes also stimulates, cell proliferation (reviewed by Yang and Moses, 2008). Furthermore, nodal signaling sometimes inhibits, whereas BMP promotes, cell differentiation, as in stem cells (Watabe and Miyazono, 2009). As TGF ligands act multifunctionally in numerous tissue types, they also play complex roles in various human diseases, ranging from autoimmune to cardiovascular diseases and cancer (reviewed by Gordon and Blobe, 2008;Massagué, 2008).Here we review the core components of the TGF family and their signaling engines, as part of a Minifocus in this issue on TGF signaling (see Box 1), and discuss emerging concepts concerning the regulatory mechanisms of TGF pathways at the receptor, cytoplasmic and nuclear level. We also highlight recent discoveries that are of particular developmental relevance. The TGF familyThe development of the axes and the asymmetry of the animal body depends on the localized action of extracellular signals, such as the Wnt, nodal and BMP ligands. Gradients of these ligands, their extracellular regulators and the competence of receptors in responding cells, play important roles during tissue morphogenesis (Affolter and Basler, 2007;Smith and Gurdon, 2004). TGF family members also contribute to tissue patterning and are important regulators of stem cell self-renewal and differentiation (see Box 2) (De Robertis and Kuroda, 2004;Watabe and Miyazono, 2009).The TGF morphogens include numerous secreted and conserved polypeptides (Table 1), which emerged at the onset of multicellular (metazoan) life (Huminiecki et al., 2009). Structurally, this family is characterized by a specific three-dimensional fold and by a conser...

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“…Mesoderm formation involves multiple pathways that act in independent, interdependent and cooperative ways (Koide et al, 2005;Loose and Patient, 2004). A second mesoderm pathway active in X. laevis involves the transcription factor p53 and its modulation of TGF signaling through interactions with SMAD proteins (Cordenonsi et al, 2003;Cordenonsi et al, 2007;Sasai et al, 2008;TakebayashiSuzuki et al, 2003). Barton et al (Barton et al, 2009) described a splice variant of the p53-related protein p63, Np63, that inhibits the p53-SMAD interaction and blocks mesoderm formation in X. laevis.…”

Section: Loss Of Mesoderm Leads To Loss Of Neural Crestmentioning

confidence: 99%

Snail2 controls mesodermal BMP/Wnt induction of neural crest

et al. 2011

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SUMMARYThe neural crest is an induced tissue that is unique to vertebrates. In the clawed frog Xenopus laevis, neural crest induction depends on signals secreted from the prospective dorsolateral mesodermal zone during gastrulation. The transcription factors Snail2 (Slug), Snail1 and Twist1 are expressed in this region. It is known that Snail2 and Twist1 are required for both mesoderm formation and neural crest induction. Using targeted blastomere injection, morpholino-based loss of function and explant studies, we show that: (1) Snail1 is also required for mesoderm and neural crest formation; (2) loss of snail1, snail2 or twist1 function in the C2/C3 lineage of 32-cell embryos blocks mesoderm formation, but neural crest is lost only in the case of snail2 loss of function; (3) snail2 mutant loss of neural crest involves mesoderm-derived secreted factors and can be rescued synergistically by bmp4 and wnt8 RNAs; and (4) loss of snail2 activity leads to changes in the RNA levels of a number of BMP and Wnt agonists and antagonists. Taken together, these results identify Snail2 as a key regulator of the signals involved in mesodermal induction of neural crest.

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Ectodermal Factor Restricts Mesoderm Differentiation by Inhibiting p53

Cited by 39 publications

References 51 publications

Regulation of p53 is critical for vertebrate limb regeneration

Regulation of p53 is critical for vertebrate limb regeneration

The regulation of TGFβ signal transduction

Snail2 controls mesodermal BMP/Wnt induction of neural crest

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