A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

Wolman, Marc A.; Jain, Roshan A.; Marsden, Kurt C.; Bell, Hannah; Skinner, Julianne; Hayer, Katharina E.; Hogenesch, John B.; Granato, Michael

doi:10.1016/j.neuron.2015.08.009

Cited by 25 publications

(88 citation statements)

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“…Next, whole mount in situ hybridization was performed after optimizing the permeabilization condition. In agreement with previous reports (Wolman et al, 2015;Miller et al, 2018), strong papp-aa mRNA signals were detected in the brain (Fig. 1D).…”

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablsupporting

confidence: 93%

“…S2). As reported by Wolman et al ( 2015), all mutant fish died around 2 weeks. Alizarin red staining indicated a complete lack of calcified bone in papp-aa -/fish ( Fig.…”

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablsupporting

confidence: 73%

“…Zebrafish has three genes belonging to the pappalysin family, papp-aa, papp-ab, andpapp-a2 (Kjaer-Sorensen et al, 2013, 2014;Wolman et al, 2015). To date, published whole mount in situ hybridization data showed that papp-aa mRNA is expressed in various neural tissues, papp-ab mRNA in developing myotomes and brain (Kjaer-Sorensen et al, 2013;Wolman et al, 2015;Miller et al, 2018;Alassaf et al, 2019), and papp-a2 in the notochord and brain (Kjaer-Sorensen et al, 2014). Because NaR cells are located on the yolk sac skin, they are more sensitive to permeabilization by protease K treatment, a key step in the whole mount in situ hybridization procedure.…”

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablmentioning

confidence: 99%

“…The possible role of Papp-aa in NaR cell reactivation was investigated by double blind experiments ( Fig. 2A) using the progeny of papp-aa +/fish intercrosses (Wolman et al, 2015, referred as pappaa p170/+ ). Under normal [Ca 2+ ] condition, NaR cell number and density among these 3 different genotype groups were similar ( Fig.…”

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablmentioning

confidence: 99%

“…Genotyping dCAPS assay and HRMA methods were used to genotype pappaa mutant. The dCAPS assay was performed following a published method (Wolman et al, 2015). Briefly, the region containing the papp-aa mutation was amplified with the dCAPS primers (Table S1), then followed by Mse1 digestion.…”

Section: Fluorescence Activated Cell Sorting (Facs) and Qpcrmentioning

confidence: 99%

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

Liu

Noer

et al. 2019

Preprint

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Human 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 [Ca 2+ ]dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca 2+transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca 2+ ] 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, Pappaa 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 [Ca 2+ ]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.

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Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablsupporting

confidence: 93%

“…S2). As reported by Wolman et al ( 2015), all mutant fish died around 2 weeks. Alizarin red staining indicated a complete lack of calcified bone in papp-aa -/fish ( Fig.…”

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablsupporting

confidence: 73%

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablmentioning

confidence: 99%

Section: Papp-aa Is Highly Expressed In Nar Cells and Is Indispensablmentioning

confidence: 99%

Section: Fluorescence Activated Cell Sorting (Facs) and Qpcrmentioning

confidence: 99%

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

Liu

Noer

et al. 2019

Preprint

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Generating Zebrafish RNA-Less Mutant Alleles by Deleting Gene Promoters with CRISPR/Cas9

Kumari

Sturgeon

Bonde

et al. 2021

Methods in Molecular Biology

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Danio rerio (zebrafish), traditionally used in forward genetic screens, has in the last decade become a popular model for reverse genetic studies with the introduction of TALENS, zinc finger nucleases, and CRISPR/Cas9. Unexpectedly, homozygous frameshift mutations generated by these tools frequently result in phenotypes that are less penetrant than those seen in embryos injected with antisense morpholino oligonucleotides targeting the same gene. One explanation for the difference is that some frameshift mutations result in nonsense-mediated decay of the gene transcript, a process which can induce expression of homologous genes. This form of genetic compensation, called transcriptional adaptation, does not occur when the mutant allele results in no RNA transcripts being produced from the targeted gene. Such RNA-less mutants can be generated by deleting a gene's promoter using a pair of guide RNAs and Cas9 protein. Here, we present a protocol and use it to generate alleles of arhgap29b and slc41a1 that lack detectable zygotic transcription. In the case of the arhgap29b mutant, an emerging phenotype did not segregate with the promoter deletion mutation, highlighting the potential for off-target mutagenesis with these tools. In summary, this chapter describes a method to generate zebrafish mutants that avoid a form of genetic compensation that occurs in many frameshift mutants.

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Acute Regulation of Habituation Learning via Posttranslational Palmitoylation

Nelson

Witze

et al. 2020

Current Biology

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A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

Cited by 25 publications

References 0 publications

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

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

Generating Zebrafish RNA-Less Mutant Alleles by Deleting Gene Promoters with CRISPR/Cas9

Acute Regulation of Habituation Learning via Posttranslational Palmitoylation

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