scholarly journals CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xidi Wang ◽  
Patrick Sipila ◽  
Zizhen Si ◽  
Jesusa L. Rosales ◽  
Xu Gao ◽  
...  
Keyword(s):  
Body Size ◽  
Developmental Disorders ◽  
Target Genes ◽  
Small Body ◽  
Human Fibroblasts ◽  
Cell Senescence ◽  
Loss Of Function ◽  
Embryonic Fibroblasts ◽  
Senescent Phenotype ◽  
Reduced Body

AbstractDevelopmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-β-gal staining compared to Cdk5rap2+/+ and Cdk5rap2+/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3β, causing increased inhibitory GSK3β Ser9 phosphorylation and inhibiting the activity of GSK3β, which phosphorylates β-catenin, tagging β-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing nuclear β-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or β-catenin causes WIP1 downregulation. Inhibition of GSK3β activity restores β-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3β activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3β/β-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.

scholarly journals Loss of Cdk5rap2 triggers cellular senescence via β-catenin-mediated downregulation of WIP1

2020 ◽  
Author(s):  
Xidi Wang ◽  
Patrick Sipila ◽  
Zizhen Si ◽  
Jesusa L. Rosales ◽  
Xu Gao ◽  
...  
Keyword(s):  
Body Size ◽  
Cellular Senescence ◽  
Developmental Disorders ◽  
Target Genes ◽  
Small Body ◽  
Human Fibroblasts ◽  
Small Body Size ◽  
Loss Of Function ◽  
Primary Microcephaly ◽  
Primordial Dwarfism

AbstractLoss-of-function mutations in Cdk5rap2 is associated with the developmental disorders, primary microcephaly and primordial dwarfism, but the underlying molecular link remains obscure. Here, we show that Cdk5rap2 loss in BJ-5ta human fibroblasts triggers senescence that is associated with proliferation defect, which is manifested as small body size in Cdk5rap2an/an mice. In fibroblasts, Cdk5rap2 loss induces p53 Ser15 phosphorylation that correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses senescence in Cdk5rap2-depleted cells, linking senescence to WIP1 downregulation. Cdk5rap2 interacts with GSK3β, increasing inhibitory Ser9 phosphorylation in GSK3β, which phosphorylates and tags β-catenin for degradation. Thus, Cdk5rap2 loss decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing β-catenin that affects expression of NF-κB target genes, including WIP1. Consequently, Cdk5rap2 or β-catenin depletion downregulates WIP1. GSK3β Inhibition in Cdk5rap2-depleted cells restores β-catenin and WIP1 levels, reducing p53 Ser15 phosphorylation and preventing senescence. Conversely, WIP1 inhibition increases p53 Ser15 phosphorylation and senescence in Cdk5rap2-depleted cells lacking GSK3β activity. Senescence through GSK3β/β-catenin downregulation of WIP1 may contribute to the developmental disorders associated with Cdk5rap2 loss-of-function.

scholarly journals Variants in FtsJ RNA 2′-O-Methyltransferase 3 and Growth Hormone 1 are associated with small body size and a dental anomaly in dogs

2020 ◽  
Vol 117 (40) ◽  
pp. 24929-24935
Author(s):  
Sydney R. Abrams ◽  
Alexandra L. Hawks ◽  
Jacquelyn M. Evans ◽  
Thomas R. Famula ◽  
Mary Mahaffey ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Size ◽  
Association Studies ◽  
Small Body ◽  
Chromosome 9 ◽  
Genome Wide Association Studies ◽  
Canine Tooth ◽  
Human Pituitary ◽  
Reduced Body

Domesticated dogs show unparalleled diversity in body size across breeds, but within breeds variation is limited by selective breeding. Many heritable diseases of dogs are found among breeds of similar sizes, suggesting that as in humans, alleles governing growth have pleiotropic effects. Here, we conducted independent genome-wide association studies in the small Shetland Sheepdog breed and discovered a locus on chromosome 9 that is associated with a dental abnormality called maxillary canine-tooth mesioversion (MCM) (P = 1.53 × 10−7) as well as two body size traits: height (P = 1.67 × 10−5) and weight (P = 1.16 × 10−7). Using whole-genome resequencing data, we identified variants in two proximal genes: FTSJ3, encoding an RNA methyltransferase, and GH1, encoding growth hormone. A substitution in FTSJ3 and a splice donor insertion in GH1 are strongly associated with MCM and reduced body size in Shetland Sheepdogs. We demonstrated in vitro that the GH1 variant leads to exon 3 skipping, predicting a mutant protein known to cause human pituitary dwarfism. Statistical modeling, however, indicates that the FTSJ3 variant is the stronger predictor of MCM and that each derived allele reduces body size by about 1 inch and 5 pounds. In a survey of 224 breeds, both FTSJ3 and GH1 variants are frequent among very small “toy” breeds and absent from larger breeds. Our findings indicate that a chromosome 9 locus harboring tightly linked variants in FTSJ3 and GH1 reduces growth in the Shetland Sheepdog and toy breed dogs and confers risk for MCM through vertical pleiotropy.

Effects of low pH and aluminum on body size, swimming performance, and susceptibility to predation of green tree frog (Hyla cinerea) tadpoles

1995 ◽  
Vol 73 (12) ◽  
pp. 2171-2183 ◽  
Author(s):  
Robin E. Jung ◽  
Charles H. Jagoe
Keyword(s):  
Body Size ◽  
Swimming Performance ◽  
Small Body ◽  
Low Ph ◽  
Analysis Of Covariance ◽  
Tree Frog ◽  
Small Body Size ◽  
Hyla Cinerea ◽  
Reduced Body ◽  
Sublethal Concentrations

Green tree frog (Hyla cinerea) tadpoles were exposed immediately after hatching to aluminum (nominally 0, 150, 250, 400 μg/L) at pH 4.5 or 5.5, plus a control (pH 7.0, 0 μg/L Al) for 96 h. Mortality increased with increasing Al concentration at pH 4.5 but not at pH 5.5. Among surviving tadpoles, body size was significantly reduced at higher Al concentrations at both pH 4.5 and 5.5. At pH 4.5, analysis of covariance indicated that maximal swimming speed was positively correlated with tadpole total length and differed among Al treatments; tadpoles at higher Al levels swam more slowly. Body Al and Na+concentrations also differed among treatments. In a second experiment, tadpoles exposed for 96 h to approximately 150 μg/L Al at 4.5 pH were preyed upon by dragonfly larvae (Libellulidae) at a higher rate than were tadpoles raised in pH 4.5 or 7.0 without Al. As in the first experiment, tadpoles exposed to Al were smaller and were slower swimmers. Sublethal concentrations of Al at low pH may result in lowered growth rates and hence reduced body size. Swimming performance is reduced by small body size, and size-adjusted performance is further reduced by Al and low pH, which might lead to higher predation on Al-stressed tadpoles.

scholarly journals Pendraig milnerae , a new small-sized coelophysoid theropod from the Late Triassic of Wales

2021 ◽  
Vol 8 (10) ◽  
Author(s):  
Stephan N. F. Spiekman ◽  
Martín D. Ezcurra ◽  
Richard J. Butler ◽  
Nicholas C. Fraser ◽  
Susannah C. R. Maidment
Keyword(s):  
Body Size ◽  
Small Body ◽  
Late Triassic ◽  
Ancestral State ◽  
Dorsal Vertebra ◽  
Left Femur ◽  
Theropod Dinosaur ◽  
Reduced Body ◽  
The Uk ◽  
Fissure Fill

We describe a new small-bodied coelophysoid theropod dinosaur, Pendraig milnerae gen. et sp. nov, from the Late Triassic fissure fill deposits of Pant-y-ffynnon in southern Wales. The species is represented by the holotype, consisting of an articulated pelvic girdle, sacrum and posterior dorsal vertebrae, and an associated left femur, and by two referred specimens, comprising an isolated dorsal vertebra and a partial left ischium. Our phylogenetic analysis recovers P. milnerae as a non-coelophysid coelophysoid theropod, representing the first-named unambiguous theropod from the Triassic of the UK. Recently, it has been suggested that Pant-y-ffynnon and other nearby Late Triassic to Early Jurassic fissure fill faunas might have been subjected to insular dwarfism. To test this hypothesis for P. milnerae , we performed an ancestral state reconstruction analysis of body size in early neotheropods. Although our results indicate that a reduced body size is autapomorphic for P. milnerae , some other coelophysoid taxa show a similar size reduction, and there is, therefore, ambiguous evidence to indicate that this species was subjected to dwarfism. Our analyses further indicate that, in contrast with averostran-line neotheropods, which increased in body size during the Triassic, coelophysoids underwent a small body size decrease early in their evolution.

A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans

Development ◽  
1999 ◽  
Vol 126 (2) ◽  
pp. 241-250 ◽  
Author(s):  
Y. Suzuki ◽  
M.D. Yandell ◽  
P.J. Roy ◽  
S. Krishna ◽  
C. Savage-Dunn ◽  
...  
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Expression Pattern ◽  
Genetic Interactions ◽  
Loss Of Function ◽  
Male Tail ◽  
C Elegans ◽  
Reduced Body ◽  
Smad Signaling Pathway ◽  
Dose Dependent

We cloned the dbl-1 gene, a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes. Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures. Conversely, dbl-1 overexpression causes markedly increased body size and partly complementary male tail phenotypes, indicating that DBL-1 acts as a dose-dependent regulator of these processes. Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway, for which DBL-1 is a previously unidentified ligand. Our study of the dbl-1 expression pattern suggests a role for neuronal cells in global size regulation as well as male tail patterning.

scholarly journals Assessment of the Growth and Reproductive Performance of Cloned Pietrain Boars

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2053
Author(s):  
Junsong Shi ◽  
Baohua Tan ◽  
Lvhua Luo ◽  
Zicong Li ◽  
Linjun Hong ◽  
...  
Keyword(s):  
Growth Rate ◽  
Body Size ◽  
Growth Performance ◽  
Reproductive Performance ◽  
Semen Quality ◽  
Small Body ◽  
Economic Benefits ◽  
Large Animal ◽  
Significant Difference ◽  
F1 Progeny

How to maximize the use of the genetic merits of the high-ranking boars (also called superior ones) is a considerable question in the pig breeding industry, considering the money and time spent on selection. Somatic cell nuclear transfer (SCNT) is one of the potential ways to answer the question, which can be applied to produce clones with genetic resources of superior boar for the production of commercial pigs. For practical application, it is essential to investigate whether the clones and their progeny keep behaving better than the “normal boars”, considering that in vitro culture and transfer manipulation would cause a series of harmful effects to the development of clones. In this study, 59,061 cloned embryos were transferred into 250 recipient sows to produce the clones of superior Pietrain boars. The growth performance of 12 clones and 36 non-clones and the semen quality of 19 clones and 28 non-clones were compared. The reproductive performance of 21 clones and 25 non-clones were also tested. Furthermore, we made a comparison in the growth performance between 466 progeny of the clones and 822 progeny of the non-clones. Our results showed that no significant difference in semen quality and reproductive performance was observed between the clones and the non-clones, although the clones grew slower and exhibited smaller body size than the non-clones. The F1 progeny of the clones showed a greater growth rate than the non-clones. Our results demonstrated through the large animal population showed that SCNT manipulation resulted in a low growth rate and small body size, but the clones could normally produce F1 progeny with excellent growth traits to bring more economic benefits. Therefore, SCNT could be effective in enlarging the merit genetics of the superior boars and increasing the economic benefits in pig reproduction and breeding.

scholarly journals Independent evolution towards larger body size in the distinctive Faroe Island mice

2021 ◽  
Author(s):  
Ricardo Wilches ◽  
William H Beluch ◽  
Ellen McConnell ◽  
Diethard Tautz ◽  
Yingguang Frank Chan
Keyword(s):  
Body Size ◽  
Meta Analysis ◽  
Small Body ◽  
Laboratory Mouse ◽  
Large Body ◽  
Natural Populations ◽  
Size Variation ◽  
Phenotypic Traits ◽  
Island Population ◽  
Multiple Loci

Abstract Most phenotypic traits in nature involve the collective action of many genes. Traits that evolve repeatedly are particularly useful for understanding how selection may act on changing trait values. In mice, large body size has evolved repeatedly on islands and under artificial selection in the laboratory. Identifying the loci and genes involved in this process may shed light on the evolution of complex, polygenic traits. Here, we have mapped the genetic basis of body size variation by making a genetic cross between mice from the Faroe Islands, which are among the largest and most distinctive natural populations of mice in the world, and a laboratory mouse strain selected for small body size, SM/J. Using this F2 intercross of 841 animals, we have identified 111 loci controlling various aspects of body size, weight and growth hormone levels. By comparing against other studies, including the use of a joint meta-analysis, we found that the loci involved in the evolution of large size in the Faroese mice were largely independent from those of a different island population or other laboratory strains. We hypothesize that colonization bottleneck, historical hybridization, or the redundancy between multiple loci have resulted in the Faroese mice achieving an outwardly similar phenotype through a distinct evolutionary path.

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