PEX11β induces peroxisomal gene expression and alters peroxisome number during early Xenopus laevis development

Fox, Mark A; Walsh, Logan A.; Nieuwesteeg, Michelle A.; Damjanovski, Sashko

doi:10.1186/1471-213x-11-24

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…The Pex11ß gene (constitutive form) contains a PPRE for PPARɣ, whereas the Pex11ɣ gene (with a yet unknown function [ 9 ]) lacks a PPRE. Interestingly, Pex11ß knockdown decreased PPARɣ, but not Pparɑ mRNA levels in Xenopus laevis oocytes [ 73 ], whereas Pex11ß overexpression increased the Pparɑ and decreased the Ppar ɣ mRNA levels [ 74 ]. In both cases, the mRNA levels of Pparß remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors

et al. 2015

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Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat), whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and related gene expression and accelerated osteoblast differentiation. Taken together, our results suggest that PPARß regulates the numerical abundance and metabolic function of peroxisomes via Pex11ß in parallel to osteoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors

et al. 2015

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“…PEX11b resides in the outer membrane of the peroxisome. It is a highly conserved peroxisomeassociated protein implicated in peroxisome replication (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although not well studied in the epidermis, peroxisomes house the metabolic enzymes for H 2 O 2 processing, fatty acid oxidation, ether lipid synthesis, and other tissue-specific metabolic functions (26,27).…”

Section: Pex11b: An Unexpected Screen Hitmentioning

confidence: 99%

Coupling organelle inheritance with mitosis to balance growth and differentiation

Asare

Levorse

Fuchs

2017

Science

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INTRODUCTION Adult tissues must balance growth and differentiation to develop and maintain homeostasis. Excessive differentiation can lead to aging and poor wound healing. Too much growth is observed in hyperproliferative disorders and cancers. How tissue imbalances arise in disease states is poorly understood. Skin is an excellent system for understanding the importance of this balance. Essential for keeping harmful microbes out and retaining body fluids, the skin barrier is maintained by an inner layer of proliferative basal progenitors, which generate a constant outward flux of terminally differentiating cells. It is known that when epidermal progenitors accumulate mutations that will give rise to malignancy, they change their program of gene expression. However, the extent to which cancer progression involves a gain of proliferation versus a loss of differentiation is unclear. A detailed molecular knowledge of how normal basal epidermal progenitors transition from a proliferative, undifferentiated state to a terminally differentiated state allows us to investigate how this process goes awry in a tumorigenic state. We use a genetic screen to identify which of the gene changes that occur in both early cell commitment and cancer are integral to maintaining the balance between growth and differentiation. RATIONALE Epithelial cancers are among the most prevalent and life-threatening cancers worldwide. Despite intensive research, the mechanisms by which these cancers evade regulatory systems working to balance differentiation and proliferation remain poorly understood. To provide new insights into how malignancies arise and how this might be exploited in advancing cancer therapeutics, we tackled this problem in the developing skin where these regulatory systems are established. RESULTS To understand how the balance between growth and differentiation is controlled, we first devised a strategy to transcriptionally profile epidermal stem cells and their terminally differentiating progeny. Using this method, we defined the earliest molecular events associated with the commitment of epidermal progenitors to their differentiation program. Of the many changes that occur, we focused on the cohort of genes that are also mutated in human epithelial cancers. To sift through which of these genes are functional drivers in cancers and how they perturb homeostasis, we conducted an in vivo epidermal RNA interference (RNAi) screen to identify candidates that are selectively enriched or depleted in proliferative progenitors relative to their differentiating progeny. We focused on PEX11b, a protein associated with peroxisomes, organelles involved in fatty acid and energy metabolism. PEX11b deficiency compromised epidermal terminal differentiation and barrier formation. Without PEX11b, peroxisomes functioned but failed to localize and therefore segregate properly during mitosis. Probing deeper, we discovered that in normal cells, peroxisomes take on stereotyped positions during mitosis. However, after depletion of PEX11b, peroxi...

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“…In addition, the Pex11p protein has been shown to mediate the transport of medium-chain fatty acids across the peroxisomal membrane, a process that indirectly affects peroxisome number and size in Saccharomyces cerevisiae ( van Roermund et al, 2000 ). Furthermore, the overexpression of PEX11β increases the expression of peroxisome-related genes, such as those encoding PEX5, catalase, PMP70 and PPARα, in Xenopus laevis ( Fox et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Deletion of a single allele of thePex11βgene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain

Ahlemeyer

Gottwald

Baumgart-Vogt

2012

Disease Models &Amp; Mechanisms

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SUMMARYImpaired neuronal migration and cell death are commonly observed in patients with peroxisomal biogenesis disorders (PBDs), and in mouse models of this diseases. In Pex11β-deficient mice, we observed that the deletion of a single allele of the Pex11β gene (Pex11β+/− heterozygous mice) caused cell death in primary neuronal cultures prepared from the neocortex and cerebellum, although to a lesser extent as compared with the homozygous-null animals (Pex11β−/− mice). In corresponding brain sections, cell death was rare, but differences between the genotypes were similar to those found in vitro. Because PEX11β has been implicated in peroxisomal proliferation, we searched for alterations in peroxisomal abundance in the brain of heterozygous and homozygous Pex11β-null mice compared with wild-type animals. Deletion of one allele of the Pex11β gene slightly increased the abundance of peroxisomes, whereas the deletion of both alleles caused a 30% reduction in peroxisome number. The size of the peroxisomal compartment did not correlate with neuronal death. Similar to cell death, neuronal development was delayed in Pex11β+/− mice, and to a further extent in Pex11β−/− mice, as measured by a reduced mRNA and protein level of synaptophysin and a reduced protein level of the mature isoform of MAP2. Moreover, a gradual increase in oxidative stress was found in brain sections and primary neuronal cultures from wild-type to heterozygous to homozygous Pex11β-deficient mice. SOD2 was upregulated in neurons from Pex11β+/− mice, but not from Pex11β−/− animals, whereas the level of catalase remained unchanged in neurons from Pex11β+/− mice and was reduced in those from Pex11β−/− mice, suggesting a partial compensation of oxidative stress in the heterozygotes, but a failure thereof in the homozygous Pex11β−/− brain. In conclusion, we report the alterations in the brain caused by the deletion of a single allele of the Pex11β gene. Our data might lead to the reconsideration of the clinical treatment of PBDs and the common way of using knockout mouse models for studying autosomal recessive diseases.

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PEX11β induces peroxisomal gene expression and alters peroxisome number during early Xenopus laevis development

Cited by 9 publications

References 33 publications

Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors

Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors

Coupling organelle inheritance with mitosis to balance growth and differentiation

Deletion of a single allele of thePex11βgene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain

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