scholarly journals The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

2019 ◽  
Author(s):  
Chengdong Liu ◽  
Shuang Li ◽  
Pernille Rimmer Noer ◽  
Kasper Kjaer-Sorensen ◽  
Caihuan Ke ◽  
...  
Keyword(s):  
Molecular Switch ◽  
Tor Signaling ◽  
Mineral Density ◽  
Zebrafish Model ◽  
Igf Binding ◽  
Underlying Mechanisms ◽  
Igf1 Receptor ◽  
Bone Calcification ◽  
Epithelial Growth ◽  
Igf Signaling

AbstractHuman patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca2+]-dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.

scholarly journals The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chengdong Liu ◽  
Shuang Li ◽  
Pernille Rimmer Noer ◽  
Kasper Kjaer-Sorensen ◽  
Anna Karina Juhl ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Tor Signaling ◽  
Mineral Density ◽  
Zebrafish Model ◽  
Bone Mass Loss ◽  
Cell Quiescence ◽  
Underlying Mechanisms ◽  
Igf1 Receptor ◽  
Bone Calcification ◽  
Igf Signaling

Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates bone calcification by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which are normally quiescent, re-enter the cell cycle under low [Ca2+] stress. Genetic deletion of Papp-aa, but not the closely related Papp-ab, abolished ionocyte proliferation and reduced calcified bone mass. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling in ionocytes. Under low Ca2+ stress, Papp-aa cleaved Igfbp5a. Under normal conditions, however, Papp-aa proteinase activity was suppressed and IGFs were sequestered in the IGF/Igfbp complex. Pharmacological disruption of the IGF/Igfbp complex or adding free IGF1 activated IGF signaling and promoted ionocyte proliferation. These findings suggest that Papp-aa-mediated local Igfbp5a cleavage functions as a [Ca2+]-regulated molecular switch linking IGF signaling to bone calcification by stimulating epithelial cell quiescence-proliferation transition under low Ca2+ stress.

scholarly journals Abnormal craniofacial and spinal bone development with col2a1a depletion in a zebrafish model of CHARGE syndrome

2020 ◽  
Author(s):  
Maximilian Breuer ◽  
Maximilian Rummler ◽  
Charlotte Zaouter ◽  
Bettina M. Willie ◽  
Shunmoogum A. Patten
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Bone Development ◽  
Morphological Changes ◽  
Charge Syndrome ◽  
Mineral Density ◽  
Zebrafish Model ◽  
Weberian Apparatus ◽  
Underlying Mechanisms ◽  
Osteoblast Markers

AbstractCHARGE syndrome patients commonly display craniofacial abnormalities. Furthermore, most patients show features of idiopathic scoliosis, reduced bone mineral density and in a few cases osteopenia. While several clinical cases and studies have documented the skeletal deformities in CHARGE syndrome bearing CHD7 mutations, the underlying mechanisms of the disorder remain elusive. Here, we detect and quantitatively analyze skeletal abnormalities in larval and adult chd7-/- zebrafish.We show that young chd7-/- larvae present with abnormal craniofacial development, especially related to cartilage. We also observe scoliosis-like spinal deformations at 9 dpf. Gene expression analysis confirmed the reduction of osteoblast markers and Pparγ targets. MicroCT analyses identified abnormal craniofacial structures, Weberian apparatus and vertebral body morphology in chd7-/- mutants, with highly mineralized inclusions, along with significant variances in bone mineral density and bone volume. Notably, we detect a specific depletion of Col2a1a in the cartilage of craniofacial regions and vertebrae, in line with a significantly reduced number of chondrocytes.Our study is the first to elucidate the mechanisms underlying morphological changes in craniofacial structure and vertebrae of adult chd7-/- zebrafish. The chd7-/- mutant zebrafish will be beneficial in future investigations of the underlying pathways of both craniofacial and spinal deformities commonly seen in CHARGE syndrome.

scholarly journals Stanniocalcin 1a is a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca2+ uptake

2020 ◽  
Author(s):  
Shuang Li ◽  
Chengdong Liu ◽  
Allison Goldstein ◽  
Yi Xin ◽  
Caihuan Ke ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Calcium Uptake ◽  
Premature Death ◽  
Tor Signaling ◽  
Zebrafish Model ◽  
Cell Reactivation ◽  
Cell Quiescence ◽  
Genetic Deletion ◽  
Signaling Activation ◽  
Igf Signaling

AbstractThe mechanisms governing cell quiescence-proliferation balance are poorly defined. Using a zebrafish model, here we report that Stc1a, a glycoprotein known as a hypocalcemic hormone, not only inhibits epithelial calcium uptake but also functions as a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance. Among the 4 stc genes, only the stc1a expression is [Ca2+]-dependent. Genetic deletion of stc1a, but not stc2b, resulted in elevated body Ca2+ contents, ectopic Ca2+ deposit, body swelling, and premature death. Reducing epithelial calcium channel Trpv6-mediated Ca2+ uptake alleviated these phenotypes. Loss of Stc1a also promoted quiescent epithelial cells to re-enter the cell cycle. This action was accompanied by local IGF signaling activation and increased expression in papp-aa, a zinc metalloproteinase degrading Igfbp5a. Genetic deletion of papp-aa or igfbp5a abolished the elevated epithelial cell reactivation in stc1a-/- mutants. Likewise, inhibition of IGF1 receptor, PI3 kinase, Akt, and Tor signaling abolished epithelial cell reactivation. These results reveal that Stc1a plays dual roles in regulating epithelial calcium uptake and cell quiescence-proliferation balance and implicate Trpv6 and Papp-aa-Igfbp5a-IGF signaling in these functions.

scholarly journals Loss of Wnt16 Leads to Skeletal Deformities and Downregulation of Bone Developmental Pathway in Zebrafish

2021 ◽  
Vol 22 (13) ◽  
pp. 6673
Author(s):  
Xiaochao Qu ◽  
Mei Liao ◽  
Weiwei Liu ◽  
Yisheng Cai ◽  
Qiaorong Yi ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Integration Site ◽  
Skeletal Development ◽  
Rna Seq ◽  
Developmental Pathway ◽  
Mineral Density ◽  
Zebrafish Model ◽  
Protein Protein Interaction ◽  
Ct Analysis

Wingless-type MMTV integration site family, member 16 (wnt16), is a wnt ligand that participates in the regulation of vertebrate skeletal development. Studies have shown that wnt16 can regulate bone metabolism, but its molecular mechanism remains largely undefined. We obtained the wnt16-/- zebrafish model using the CRISPR-Cas9-mediated gene knockout screen with 11 bp deletion in wnt16, which led to the premature termination of amino acid translation and significantly reduced wnt16 expression, thus obtaining the wnt16-/- zebrafish model. The expression of wnt16 in bone-related parts was detected via in situ hybridization. The head, spine, and tail exhibited significant deformities, and the bone mineral density and trabecular bone decreased in wnt16-/- using light microscopy and micro-CT analysis. RNA sequencing was performed to explore the differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the down-regulated DEGs are mainly concentrated in mTOR, FoxO, and VEGF pathways. Protein–protein interaction (PPI) network analysis was performed with the detected DEGs. Eight down-regulated DEGs including akt1, bnip4, ptena, vegfaa, twsg1b, prkab1a, prkab1b, and pla2g4f.2 were validated by qRT-PCR and the results were consistent with the RNA-seq data. Overall, our work provides key insights into the influence of wnt16 gene on skeletal development.

Plasmalogens improve swimming performance by modulating the expression of genes involved in amino acids and lipid metabolism, oxidative stress, and ferroptosis in an Alzheimer's disease zebrafish model

2021 ◽  
Author(s):  
Junli Feng ◽  
Gongshuai Song ◽  
Yuanyuan Wu ◽  
Xi Chen ◽  
Jie Pang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acids ◽  
Lipid Metabolism ◽  
Human Health ◽  
Swimming Performance ◽  
Cognitive Impairments ◽  
Zebrafish Model ◽  
Expression Of Genes ◽  
Health Studies ◽  
Underlying Mechanisms

Plasmalogens (PLs) are critical to human health. Studies have reported a link between downregulation of PLs levels and cognitive impairments in patients with Alzheimer´s disease (AD). however, the underlying mechanisms...

scholarly journals Elevated free IGF2 levels in localized, early-stage breast cancer in women

2008 ◽  
Vol 159 (5) ◽  
pp. 595-601 ◽  
Author(s):  
Ulrick Espelund ◽  
Søren Cold ◽  
Jan Frystyk ◽  
Hans Ørskov ◽  
Allan Flyvbjerg
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Serum Levels ◽  
Epidemiological Studies ◽  
Early Stage Breast Cancer ◽  
Cancer Disease ◽  
Igf Binding ◽  
Localized Disease ◽  
Igf1 Receptor ◽  
Igf Binding Protein

ObjectiveEpidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease.DesignThe participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured.ResultsIn patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (−12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (−16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged.ConclusionWomen with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.

scholarly journals Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3329-3340 ◽  
Author(s):  
Niccolò Bolli ◽  
Elspeth M. Payne ◽  
Clemens Grabher ◽  
Jeong-Soo Lee ◽  
Adam B. Johnston ◽  
...  
Keyword(s):  
Hematopoietic Cells ◽  
Model Organism ◽  
Myeloid Cell ◽  
Wild Type ◽  
Zebrafish Model ◽  
Blood Island ◽  
Cell Numbers ◽  
Myeloid Leukemias ◽  
Underlying Mechanisms ◽  
Ventral Wall

AbstractMutations in the human nucleophosmin (NPM1) gene are the most frequent genetic alteration in adult acute myeloid leukemias (AMLs) and result in aberrant cytoplasmic translocation of this nucleolar phosphoprotein (NPMc+). However, underlying mechanisms leading to leukemogenesis remain unknown. To address this issue, we took advantage of the zebrafish model organism, which expresses 2 genes orthologous to human NPM1, referred to as npm1a and npm1b. Both genes are ubiquitously expressed, and their knockdown produces a reduction in myeloid cell numbers that is specifically rescued by NPM1 expression. In zebrafish, wild-type human NPM1 is nucleolar while NPMc+ is cytoplasmic, as in human AML, and both interact with endogenous zebrafish Npm1a and Npm1b. Forced NPMc+ expression in zebrafish causes an increase in pu.1+ primitive early myeloid cells. A more marked perturbation of myelopoiesis occurs in p53m/m embryos expressing NPMc+, where mpx+ and csf1r+ cell numbers are also expanded. Importantly, NPMc+ expression results in increased numbers of definitive hematopoietic cells, including erythromyeloid progenitors in the posterior blood island and c-myb/cd41+ cells in the ventral wall of the aorta. These results are likely to be relevant to human NPMc+ AML, where the observed NPMc+ multilineage expression pattern implies transformation of a multipotent stem or progenitor cell.

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