Loss of Citron Kinase Affects a Subset of Progenitor Cells That Alters Late but Not Early Neurogenesis in the Developing Rat Retina

Karunakaran, Devi Krishna Priya; Chhaya, Nisarg; Lemoine, Christopher; Congdon, Sean; Black, Amye; Kanadia, Rahul N.

doi:10.1167/iovs.14-15272

Cited by 7 publications

(7 citation statements)

References 34 publications

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“…Collectively, the synergistic effects shown in Figure 7 are consistent with previously reported findings in the use of large amino acid transporter 1 for delivering drugs to glioblastoma under in vivo settings. 21,41 3.11. In Vivo Toxicity Studies.…”

Section: Resultsmentioning

confidence: 99%

Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5β1 Integrin Receptor-Selective Liposomes

et al. 2020

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Glioblastoma multiforme (GBM) is one of the most aggressive tumors with a median survival of only 15 months. Effective therapeutics need to overcome the formidable challenge of crossing the blood–brain barrier (BBB). Receptors and transporters overexpressed on BCECs are being used for designing liposomes, polymers, polymeric micelles, peptides, and dendrimer-based drug carriers for combating brain tumors. Herein, using the orthotopic mouse glioblastoma model, we show that codelivering a small-molecule inhibitor of the JAK/STAT pathway (WP1066) and STAT3siRNA with nanometric (100–150 nm) α5β1 integrin receptor-selective liposomes of RGDK-lipopeptide holds therapeutic promise in combating glioblastoma. Rh-PE (red)-labeled liposomes of RGDK-lipopeptide were found to be internalized in GL261 cells via integrin α5β1 receptors. Intravenously administered near-infrared (NIR)-dye-labeled α5β1 integrin receptor-selective liposomes of RGDK-lipopeptide were found to be accumulated preferentially in the mouse brain tumor tissue. Importantly, we show that iv injection of WP1066 (a commercially sold small-molecule inhibitor of the JAK/STAT pathway) and STAT3siRNA cosolubilized within the liposomes of RGDK-lipopeptide leads to significant inhibition (>350% compared to the untreated mice group) of orthotopically growing mouse glioblastoma. The present strategy may find future use in combating GBM.

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Section: Resultsmentioning

confidence: 99%

Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5β1 Integrin Receptor-Selective Liposomes

et al. 2020

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“…The slides were then washed five times with PBT, followed by three PBS washes and mounting with ProLong Gold Antifade Mountant (Thermo Fisher Scientific, P36930). For all other antibodies, staining was performed as described in (Karunakaran et al, 2015). Primary antibodies were diluted to 1:50 (mouse anti-CRIK/CITK, BD Biosciences, 611376; rabbit anti-cyclin B1, Cell Signaling Technology, 4138; MoBu-1 clone mouse anti-BrdU, Santa Cruz Biotechnology, sc-51514), 1:100 (mouse anti-Aurora-B/AIM1, BD Biosciences, 611082; mouse anti-Pax6, Developmental Studies Hybridoma Bank, PAX6-b), 1:200 (mouse anti-γH2AX, MilliporeSigma, 05-636; rabbit anti-NeuN, Abcam, ab17787), 1:300 (rabbit anti-cleaved caspase 3, Cell Signaling Technology, 9665S; mouse anti-KI67, BD Biosciences, 556003; rabbit anti-p53, Leica Microsystems, p53-CM5p; rabbit anti-Pax6, MilliporeSigma, AB2237), or 1:500 (rabbit anti-PH3, Bethyl Laboratories, IHC-00061; rabbit anti-TBR2, Abcam, ab23345).…”

Section: Ifmentioning

confidence: 99%

Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells

et al. 2018

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Mutation in minor spliceosome components is linked to the developmental disorder microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Here, we inactivated the minor spliceosome in the developing mouse cortex (pallium) by ablating , which encodes the crucial minor spliceosome small nuclear RNA (snRNA) U11. conditional knockout mice were born with microcephaly, which was caused by the death of self-amplifying radial glial cells (RGCs), while intermediate progenitor cells and neurons were produced. RNA sequencing suggested that this cell death was mediated by upregulation of p53 (Trp53 - Mouse Genome Informatics) and DNA damage, which were both observed specifically in U11-null RGCs. Moreover, U11 loss caused elevated minor intron retention in genes regulating the cell cycle, which was consistent with fewer RGCs in S-phase and cytokinesis, alongside prolonged metaphase in RGCs. In all, we found that self-amplifying RGCs are the cell type most sensitive to loss of minor splicing. Together, these findings provide a potential explanation of how disruption of minor splicing might cause microcephaly in MOPD1.

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“…We used 10 μm limb bud cryosections for IF as described previously (Karunakaran et al, 2015). Primary antibodies were diluted to 1:50 (MoBu-1 clone mouse anti-BrdU, Santa Cruz Biotechnology, sc-51514), 1:100 (mouse anti-Aurora-B/AIM1, BD Biosciences, 611082) or 1:500 (rabbit anti-PH3, Bethyl Laboratories, IHC-00061).…”

Section: Ifmentioning

confidence: 99%

Loss of U11 small nuclear RNA in the developing mouse limb results in micromelia

et al. 2020

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Disruption of the minor spliceosome due to mutations in RNU4ATAC is linked to primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1, Roifman syndrome, and Lowry-Wood syndrome. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite being vital for limb development and size regulation, its role remains unexplored. Here, we disrupt minor spliceosome function in the developing mouse limb by ablating one of its essential components, U11 small nuclear RNA, which resulted in micromelia. Notably, earlier loss of U11 corresponded to increased severity. We find that limb size is reduced owing to elevated minor intron retention in minor intron-containing genes that regulate cell cycle. As a result, limb progenitor cells experience delayed prometaphase-to-metaphase transition and prolonged S-phase. Moreover, we observed death of rapidly dividing, distally located progenitors. Despite cell cycle defects and cell death, the spatial expression of key limb patterning genes was maintained. Overall, we show that the minor spliceosome is required for limb development via size control potentially shared in disease and domestication.

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Loss of Citron Kinase Affects a Subset of Progenitor Cells That Alters Late but Not Early Neurogenesis in the Developing Rat Retina

Abstract: Our study showed that CitK is not required for a subset of RPCs before E14, but is necessary for RPC survival post E14. This in turn results in normal early embryonic neurogenesis, but severely compromised later embryonic and postnatal neurogenesis.

Cited by 7 publications

References 34 publications

Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5β1 Integrin Receptor-Selective Liposomes

Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5β1 Integrin Receptor-Selective Liposomes

Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells

Loss of U11 small nuclear RNA in the developing mouse limb results in micromelia

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