scholarly journals Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis

2021 ◽  
Author(s):  
William B. Barrell ◽  
Hadeel Adel Al-Lami ◽  
Jacqueline A. C. Goos ◽  
Sigrid M. A. Swagemakers ◽  
Marieke van Dooren ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Monozygotic Twins ◽  
Negative Regulator ◽  
Critical Periods ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Direct Role ◽  
Pathway Activation ◽  
Novel Variant ◽  
The Brain

AbstractCraniosynostosis is a birth defect occurring in approximately one in 2000 live births, where premature fusion of the cranial bones inhibits growth of the skull during critical periods of brain development. The resulting changes in skull shape can lead to compression of the brain, causing severe complications. While we have some understanding of the molecular pathology of craniosynostosis, a large proportion of cases are of unknown genetic aetiology. Based on studies in mouse, we previously proposed that the ciliopathy gene Fuz should be considered a candidate craniosynostosis gene. Here, we report a novel variant of FUZ (c.851 G > C, p.(Arg284Pro)) found in monozygotic twins presenting with craniosynostosis. To investigate whether Fuz has a direct role in regulating osteogenic fate and mineralisation, we cultured primary osteoblasts and mouse embryonic fibroblasts (MEFs) from Fuz mutant mice. Loss of Fuz resulted in increased osteoblastic mineralisation. This suggests that FUZ protein normally acts as a negative regulator of osteogenesis. We then used Fuz mutant MEFs, which lose functional primary cilia, to test whether the FUZ p.(Arg284Pro) variant could restore FUZ function during ciliogenesis. We found that expression of the FUZ p.(Arg284Pro) variant was sufficient to partially restore cilia numbers, but did not mediate a comparable response to Hedgehog pathway activation. Together, this suggests the osteogenic effects of FUZ p.(Arg284Pro) do not depend upon initiation of ciliogenesis.

scholarly journals Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis

2019 ◽  
Vol 116 (15) ◽  
pp. 7471-7476 ◽  
Author(s):  
Urbain Weyemi ◽  
Bindu D. Paul ◽  
Deeya Bhattacharya ◽  
Adarsha P. Malla ◽  
Myriem Boufraqech ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Ectopic Expression ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Histone H2ax ◽  
Mitochondrial Homeostasis ◽  
Neurobehavioral Deficits ◽  
Mutant Cells ◽  
The Brain

Phosphorylation of histone H2AX is a major contributor to efficient DNA repair. We recently reported neurobehavioral deficits in mice lacking H2AX. Here we establish that this neural failure stems from impairment of mitochondrial function and repression of the mitochondrial biogenesis gene PGC-1α. H2AX loss leads to reduced levels of the major subunits of the mitochondrial respiratory complexes in mouse embryonic fibroblasts and in the striatum, a brain region particularly vulnerable to mitochondrial damage. These defects are substantiated by disruption of the mitochondrial shape in H2AX mutant cells. Ectopic expression of PGC-1α restores mitochondrial oxidative phosphorylation complexes and mitigates cell death. H2AX knockout mice display increased neuronal death in the brain when challenged with 3-nitropronionic acid, which targets mitochondria. This study establishes a role for H2AX in mitochondrial homeostasis associated with neuroprotection.

scholarly journals Arl13b regulates Shh signaling from both inside and outside the cilium

2016 ◽  
Vol 27 (23) ◽  
pp. 3780-3790 ◽  
Author(s):  
Laura E. Mariani ◽  
Maarten F. Bijlsma ◽  
Anna A. Ivanova ◽  
Sarah K. Suciu ◽  
Richard A. Kahn ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Primary Cilia ◽  
Null Allele ◽  
Joubert Syndrome ◽  
Missense Mutations ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Shh Signaling ◽  
Localization Signal ◽  
Palmitoylation Site

The regulatory GTPase Arl13b localizes to primary cilia, where it regulates Sonic hedgehog (Shh) signaling. Missense mutations in ARL13B can cause the ciliopathy Joubert syndrome (JS), and the mouse null allele is embryonic lethal. We used mouse embryonic fibroblasts as a system to determine the effects of Arl13b mutations on Shh signaling. We tested seven different mutants—three JS-causing variants, two point mutants predicted to alter guanine nucleotide handling, one that disrupts cilia localization, and one that prevents palmitoylation and thus membrane binding—in assays of transcriptional and nontranscriptional Shh signaling. We found that mutations disrupting Arl13b’s palmitoylation site, cilia localization signal, or GTPase handling altered the Shh response in distinct assays of transcriptional or nontranscriptional signaling. In contrast, JS-causing mutations in Arl13b did not affect Shh signaling in these same assays, suggesting that these mutations result in more subtle defects, likely affecting only a subset of signaling outputs. Finally, we show that restricting Arl13b from cilia interferes with its ability to regulate Shh-stimulated chemotaxis, despite previous evidence that cilia themselves are not required for this nontranscriptional Shh response. This points to a more complex relationship between the ciliary and nonciliary roles of this regulatory GTPase than previously envisioned.

scholarly journals Regulation of c-Fos Gene Expression by NF-κB: A p65 Homodimer Binding Site in Mouse Embryonic Fibroblasts but Not Human HEK293 Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e84062 ◽  
Author(s):  
Yu-Cheng Tu ◽  
Duen-Yi Huang ◽  
Shine-Gwo Shiah ◽  
Jang-Shiun Wang ◽  
Wan-Wan Lin
Keyword(s):  
Gene Expression ◽  
Binding Site ◽  
Hek293 Cells ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts

scholarly journals Introduction of Mouse Embryonic Fibroblasts into Early Embryos: From Confusion to Constructive Discussion. Comment on Savatier, P. Introduction of Mouse Embryonic Fibroblasts into Early Embryos Causes Reprogramming and (Con)fusion. Cells 2021, 10, 772

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1534
Author(s):  
Krystyna Żyżyńska-Galeńska ◽  
Jolanta Karasiewicz ◽  
Agnieszka Bernat
Keyword(s):  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Early Embryos ◽  
Constructive Discussion

We would like to address the issues raised by Pierre Savatier in “Introduction of Mouse Embryonic Fibroblasts into Early Embryos Causes Reprogramming and (Con)Fusion” [...]

616 Mouse Embryonic Fibroblasts Null for the KrüPpel-Like Factor 4 Alleles Are Genetically Unstable

2008 ◽  
Vol 134 (4) ◽  
pp. A-86
Author(s):  
Engda G. Hagos ◽  
Amr Ghaleb ◽  
W Brian Dalton ◽  
Jonathan P. Katz ◽  
Klaus H. Kaestner ◽  
...  
Keyword(s):  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts

scholarly journals Introduction of Mouse Embryonic Fibroblasts into Early Embryos Causes Reprogramming and (Con)fusion

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 772
Author(s):  
Pierre Savatier
Keyword(s):  
Somatic Cell ◽  
Cell Nuclei ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Early Embryos

The reprogramming of somatic cell nuclei to achieve pluripotency is one of the most important biological discoveries of the last few decades [...]

scholarly journals Programming of the reproductive axis by hormonal and genetic manipulation in mice

Reproduction ◽  
2018 ◽  
Author(s):  
Susana B Rulli ◽  
María Julia Cambiasso ◽  
Laura D Ratner
Keyword(s):  
Sex Chromosome ◽  
Genetic Manipulation ◽  
Sex Differentiation ◽  
Reproductive Function ◽  
Gonadal Steroids ◽  
Critical Periods ◽  
Female Reproduction ◽  
Control Male ◽  
Male And Female ◽  
The Brain

In mammals, the reproductive function is controlled by the hypothalamic-pituitary-gonadal axis. During development, mechanisms mediated by gonadal steroids exert an imprinting at the hypothalamic-pituitary level, by establishing sexual differences in the circuits that control male and female reproduction. In rodents, the testicular production of androgens increases drastically during the fetal/neonatal stage. This process is essential for the masculinization of the reproductive tract, genitals and brain. The conversion of androgens to estrogens in the brain is crucial for the male sexual differentiation and behavior. Conversely, feminization of the brain occurs in the absence of high levels of gonadal steroids during the perinatal period in females. Potential genetic contribution to the differentiation of brain cells through direct effects of genes located on sex chromosomes is also relevant. In this review, we will focus on the phenotypic alterations that occur on the hypothalamic-pituitary-gonadal axis of transgenic mice with persistently elevated expression of the human chorionic gonadotropin hormone (hCG). Excess of endogenously synthesized gonadal steroids due to a constant hCG stimulation is able to disrupt the developmental programming of the hypothalamic-pituitary axis in both transgenic males and females. Locally produced estrogens by the hypothalamic aromatase might play a key role in the phenotype of these mice. The “four core genotypes” mouse model demonstrated a potential influence of sex chromosome genes in brain masculinization before critical periods of sex differentiation. Thus, hormonal and genetic factors interact to regulate the local production of the neurosteroids necessary for the programming of the male and female reproductive function.

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