Faculty Opinions recommendation of Mouse development and cell proliferation in the absence of D-cyclins.

ABSTRACT The Pax transactivation domain-interacting protein (PTIP) is a large nuclear protein with multiple BRCT domains that was identified on the basis of its interaction with transcription factors of the Pax and Smad families. To address the function of PTIP during mouse development, we generated a constitutive null allele. Homozygous PTIP mutants are developmentally retarded, disorganized, and embryonic lethal by day 9.5 of embryonic development (E9.5). PTIP mutant cells appear to replicate DNA but show reduced levels of mitosis and widespread cell death by E8.5. DNA damage appears to precede nuclear condensation at E7.5, suggesting a defect in DNA repair. Neither embryonic fibroblast nor embryonic stem cells from PTIP mutants proliferate in culture, suggesting a fundamental defect in cell proliferation. Trophoblast cells from PTIP mutants are more sensitive to DNA-damaging agents. Condensation of chromatin and expression of phospho-histone H3 are also affected in PTIP mutants, and this may underlie the inability of PTIP mutants to progress through mitosis. Given the role of BRCT domain proteins in DNA repair and cell cycle control, we propose that PTIP is an essential element of the cell proliferation machinery, perhaps by functioning in the DNA repair pathways.

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Redundant Roles of Tead1 and Tead2 in Notochord Development and the Regulation of Cell Proliferation and Survival

Molecular and Cellular Biology ◽

10.1128/mcb.01759-07 ◽

2008 ◽

Vol 28 (10) ◽

pp. 3177-3189 ◽

Cited By ~ 107

Author(s):

Atsushi Sawada ◽

Hiroshi Kiyonari ◽

Kanako Ukita ◽

Noriyuki Nishioka ◽

Yu Imuta ◽

...

Keyword(s):

Cell Proliferation ◽

Paraxial Mesoderm ◽

Mouse Development ◽

Lateral Plate ◽

Growth Defects ◽

Mouse Mutants ◽

Severe Growth

ABSTRACT Four members of the TEAD/TEF family of transcription factors are expressed widely in mouse embryos and adult tissues. Although in vitro studies have suggested various roles for TEAD proteins, their in vivo functions remain poorly understood. Here we examined the role of Tead genes by generating mouse mutants for Tead1 and Tead2. Tead2 −/− mice appeared normal, but Tead1 −/−; Tead2 −/− embryos died at embryonic day 9.5 (E9.5) with severe growth defects and morphological abnormalities. At E8.5, Tead1 −/−; Tead2 −/− embryos were already small and lacked characteristic structures such as a closed neural tube, a notochord, and somites. Despite these overt abnormalities, differentiation and patterning of the neural plate and endoderm were relatively normal. In contrast, the paraxial mesoderm and lateral plate mesoderm were displaced laterally, and a differentiated notochord was not maintained. These abnormalities and defects in yolk sac vasculature organization resemble those of mutants for Yap, which encodes a coactivator of TEAD proteins. Moreover, we demonstrated genetic interactions between Tead1 and Tead2 and Yap. Finally, Tead1 −/−; Tead2 −/− embryos showed reduced cell proliferation and increased apoptosis. These results suggest that Tead1 and Tead2 are functionally redundant, use YAP as a major coactivator, and support notochord maintenance as well as cell proliferation and survival in mouse development.

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Crucial Role for Mst1 and Mst2 Kinases in Early Embryonic Development of the Mouse

Molecular and Cellular Biology ◽

10.1128/mcb.00551-09 ◽

2009 ◽

Vol 29 (23) ◽

pp. 6309-6320 ◽

Cited By ~ 79

Author(s):

Sangphil Oh ◽

Dongjun Lee ◽

Tackhoon Kim ◽

Tae-Shin Kim ◽

Hyun Jung Oh ◽

...

Keyword(s):

Cell Proliferation ◽

Single Copy ◽

Mutant Mice ◽

Placental Development ◽

Mouse Development ◽

Proliferating Cells ◽

Vascular Patterning ◽

Primitive Hematopoiesis ◽

Early Mouse

ABSTRACT Mammalian sterile 20-like kinases 1 and 2 (Mst1 and Mst2, respectively) are potent serine/threonine kinases that are involved in cell proliferation and cell death. To investigate the physiological functions of Mst1 and Mst2, we generated Mst1 and Mst2 mutant mice. Mst1 −/− and Mst2 −/− mice were viable and fertile and developed normally, suggesting possible functional overlaps between the two genes. A characterization of heterozygous and homozygous combinations of Mst1 and Mst2 mutant mice showed that mice containing a single copy of either gene underwent normal organ development; however, Mst1 −/−; Mst2 −/− mice lacking both Mst1 and Mst2 genes started dying in utero at approximately embryonic day 8.5. Mst1 −/−; Mst2 −/− mice exhibited severe growth retardation, failed placental development, impaired yolk sac/embryo vascular patterning and primitive hematopoiesis, increased apoptosis in placentas and embryos, and disorganized proliferating cells in the embryo proper. These findings indicate that both Mst1 and Mst2 kinases play essential roles in early mouse development, regulating placental development, vascular patterning, primitive hematopoiesis, and cell proliferation and survival.

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E2f3a and E2f3b Contribute to the Control of Cell Proliferation and Mouse Development

Molecular and Cellular Biology ◽

10.1128/mcb.01161-08 ◽

2008 ◽

Vol 29 (2) ◽

pp. 414-424 ◽

Cited By ~ 54

Author(s):

Jean-Leon Chong ◽

Shih-Yin Tsai ◽

Nidhi Sharma ◽

Rene Opavsky ◽

Richard Price ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Progression ◽

Specific Gene ◽

Mouse Development ◽

Double Knockout ◽

Proliferation And Apoptosis ◽

The Individual ◽

Redundant Functions

ABSTRACT The E2f3 locus encodes two Rb-binding gene products, E2F3a and E2F3b, which are differentially regulated during the cell cycle and are thought to be critical for cell cycle progression. We targeted the individual inactivation of E2f3a or E2f3b in mice and examined their contributions to cell proliferation and development. Chromatin immunoprecipitation and gene expression experiments using mouse embryo fibroblasts deficient in each isoform showed that E2F3a and E2F3b contribute to G1/S-specific gene expression and cell proliferation. Expression of E2f3a or E2f3b was sufficient to support E2F target gene expression and cell proliferation in the absence of other E2F activators, E2f1 and E2f2, suggesting that these isoforms have redundant functions. Consistent with this notion, E2f3a −/− and E2f3b −/− embryos developed normally, whereas embryos lacking both isoforms (E2f3 −/−) died in utero. We also find that E2f3a and E2f3b have redundant and nonredundant roles in the context of Rb mutation. Analysis of double-knockout embryos suggests that the ectopic proliferation and apoptosis in Rb −/− embryos is mainly mediated by E2f3a in the placenta and nervous system and by both E2f3a and E2f3b in lens fiber cells. Together, we conclude that the contributions of E2F3a and E2F3b in cell proliferation and development are context dependent.

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JunB can substitute for Jun in mouse development and cell proliferation

Nature Genetics ◽

10.1038/ng790 ◽

2002 ◽

Vol 30 (2) ◽

pp. 158-166 ◽

Cited By ~ 95

Author(s):

Emmanuelle Passegué ◽

Wolfram Jochum ◽

Axel Behrens ◽

Romeo Ricci ◽

Erwin F. Wagner

Keyword(s):

Cell Proliferation ◽

Mouse Development

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Gadd45γ Is Dispensable for Normal Mouse Development and T-Cell Proliferation

Molecular and Cellular Biology ◽

10.1128/mcb.21.9.3137-3143.2001 ◽

2001 ◽

Vol 21 (9) ◽

pp. 3137-3143 ◽

Cited By ~ 27

Author(s):

Angelika Hoffmeyer ◽

Roland Piekorz ◽

Richard Moriggl ◽

James N. Ihle

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Normal Mouse ◽

Interleukin 2 ◽

Family Members ◽

Growth Control ◽

Physiological Role ◽

T Cell Proliferation ◽

Mouse Development ◽

Peripheral T Cells

ABSTRACT Gadd45γ, a family member of the growth arrest and DNA damage-inducible gene family 45 (Gadd45), is strongly induced by interleukin-2 (IL-2) in peripheral T cells. While in most tissues all Gadd45 family members are expressed, Gadd45γ is the only member that is induced by IL-2. Here we show that the IL-2-induced expression of Gadd45γ is dependent on a signaling pathway mediated by the tyrosine kinase Jak3 and the transcription factors Stat5a and Stat5b (signal transducer and activator of transcription). Previous studies with ectopically overexpressed Gadd45γ in various cell lines implicated its function in negative growth control. To analyze the physiological role of Gadd45γ we used homologous recombination to generate mice lacking Gadd45γ. Gadd45γ-deficient mice develop normally, are indistinguishable from their littermates, and are fertile. Furthermore, hematopoiesis in mice lacking Gadd45γ is not impaired and Gadd45γ-deficient T lymphocytes show normal responses to IL-2. These data demonstrate that Gadd45γ is not essential for normal mouse development and hematopoiesis, possibly due to functional redundancy among the Gadd45 family members. Gadd45γ is also dispensable for IL-2-induced T-cell proliferation.

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