Caspases are enzymes with protease activity. Despite being known for more than three decades, caspase investigation still yields surprising and fascinating information. Initially associated with cell death and inflammation, their functions have gradually been revealed to extend beyond, targeting pathways such as cell proliferation, migration, and differentiation. These processes are also associated with disease mechanisms, positioning caspases as potential targets for numerous pathologies including inflammatory, neurological, metabolic, or oncological conditions. While in vitro studies play a crucial role in elucidating molecular pathways, they lack the context of the body's complexity. Therefore, laboratory animals are an indispensable part of successfully understanding and applying caspase networks. This paper aims to summarize and discuss recent knowledge, understanding, and challenges in caspase knock-out mice.

• MeSH
• apoptóza MeSH
• kaspasy * metabolismus   genetika   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované * MeSH
• myši MeSH
• zánět enzymologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

• MeSH
• apoptóza MeSH
• crista neuralis patologie   MeSH
• fenotyp MeSH
• kraniofaciální abnormality * genetika   patologie   MeSH
• lidé MeSH
• mandibulofaciální dysostóza * genetika   MeSH
• mutageneze MeSH
• myši MeSH
• ribozomy genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

T-2 toxin, a major compound of trichothecenes, inhibits protein synthesis and induces inflammation and cell apoptosis through the activation of MAPK pathway. The JAK/STAT pathway has recently been shown to be downstream targets of trichothecenes. However, whether there is any crosstalk between JNK and JAK/STAT pathways in trichothecene toxicity has not been studied. In the present study, we explored this potential in RAW264.7 cells treated with T-2 toxin. Our results revealed a crosstalk between JNK1 and STAT3 after T-2 toxin treatment, which was mediated by K-Ras. T-2 toxin treatment resulted in rapid phosphorylation, and more importantly, JNK1-STAT3 signaling pathway was shown to maintain the normal function of the mitochondria and to inhibit T-2 toxin-induced apoptosis. Therefore, this pathway was considered to be a potential cell survival pathway. Breakdown and degranulation of ribosomes in the rough endoplasmic reticulum and swelling of mitochondria were clearly visible after the cells had been incubated with T-2 toxin for 12h. Our data suggest that T-2 toxin had a Janus face: it induced both apoptotic and cell survival pathways. These results suggest that the crosstalk and the balance between MAPK and JAK/STAT pathway might be involved in T-2 toxin-induced apoptosis in RAW264.7 cells.

• MeSH
• anthraceny farmakologie   MeSH
• apoptóza účinky léků   MeSH
• biologické modely MeSH
• buněčné linie MeSH
• cytokiny genetika   metabolismus   MeSH
• fluorescenční protilátková technika MeSH
• fosforylace účinky léků   MeSH
• Janus kinasy metabolismus   MeSH
• kinetika MeSH
• makrofágy cytologie   účinky léků   metabolismus   ultrastruktura   MeSH
• mitochondrie účinky léků   metabolismus   ultrastruktura   MeSH
• mitogenem aktivovaná proteinkinasa 8 metabolismus   MeSH
• myši MeSH
• ras proteiny metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• ribozomy účinky léků   metabolismus   ultrastruktura   MeSH
• signální transdukce * účinky léků   MeSH
• T-2 toxin farmakologie   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH