Project description:The number of vertebrae is precisely defined in almost all vertebrate species, but varies considerably in pigs, making this animal an excellent model for studying the mechanisms that control vertebral number. Vertnin (VRTN) variants have been associated with thoracic vertebral number (TVN) in pigs. However, the causal relation between VRTN and TVN remains to be established, and the role of VRTN in modulating TVN is not yet known. Here, we demonstrate that VRTN is one of the genes responsible for determining TVN. We show that VRTN is a DNA-binding transcription factor, which is essential for the formation of thoracic vertebrae during early embryogenesis as VRTN-null mice showed embryonic lethality at the later thoracic somite stages and had fewer somites than their wild-type and heterozygous littermates. We also show that VRTN causative variants increase Notch signaling in pig embryos, suggesting that VRTN controls segment number by altering the pace of somatic segmentation. These findings advance our understanding of the role of VRTN in the formation of thoracic vertebrae and reveal new aspects of somite developmental biology.
Project description:The number of vertebrae is precisely defined in almost all vertebrate species, but varies considerably in pigs, making this animal an excellent model for studying the mechanisms that control vertebral number. Vertnin (VRTN) variants have been associated with thoracic vertebral number (TVN) in pigs. However, the causal relation between VRTN and TVN remains to be established, and the role of VRTN in modulating TVN is not yet known. Here, we demonstrate that VRTN is one of the genes responsible for determining TVN. We show that VRTN is a DNA-binding transcription factor, which is essential for the formation of thoracic vertebrae during early embryogenesis as VRTN-null mice showed embryonic lethality at the later thoracic somite stages and had fewer somites than their wild-type and heterozygous littermates. We also show that VRTN causative variants increase Notch signaling in pig embryos, suggesting that VRTN controls segment number by altering the pace of somatic segmentation. These findings advance our understanding of the role of VRTN in the formation of thoracic vertebrae and reveal new aspects of somite developmental biology.
Project description:Intratumor mutational heterogeneity has been documented in primary non-small cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC-mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk germline APOBEC3 variant, strongly correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN- induced expression of APOBEC3B in lung adenocarcinoma cells in culture suggesting a role for the immune microenvironment in the generation of mutational heterogeneity. CNA occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.
Project description:Hypertension, atherosclerosis, and aneurysms alter thoracic aorta structure. Aortic lesions found in these diseases show a unique anatomical distribution. For instance, calcifications and atherosclerotic lesions tend to occur more frequently in the posterior wall of the aorta compared to other regions. The role that the outer layer of the aorta, its perivascular adipose tissue (PVAT), plays in the pathogenesis of these lesions is unknown. The descending thoracic aorta's PVAT is distributed in three strips of tissue: one strip is located anterior to the aorta (AP), while the other two are positioned laterally to the vessel and are adjacent to the thoracic vertebrae (LP). Genetic tracing indicates LP's adipocytes descend from sm22a+ and Myf5+ progenitors while the anterior are from sm22a+ only. The implications of this ontology and aortic PVAT distribution on the development of adipocytes are unknown. We hypothesize that the anatomical location of adipocyte progenitors influences their adipogenic potential. PVAT from LP and AP was collected from male SD rats at 10 wks of age (n=7) to harvest progenitors by outgrowth expansion. Progenitors were differentiated for 4 d in adipogenic media. Adipogenesis was evaluated by lipid droplet and triglyceride quantification using the IncuCyte Live-Cell® system. RNA from progenitors and adipocytes was sequenced in Illumina NextSeqData, and Differential Expressed Genes (DEG) identified. Enrichment and network analyses were performed in Ingenuity Pathways (IPA). Our findings provide evidence supporting differences in adipogenic activity and extracellular matrix secretion between the LP and AP PVAT of the aorta. These differences may explain the anatomical location of aortic lesions associated with hypertension, atherosclerosis, and aneurysms.
Project description:Analysis of expression changes in prelabeled laser-microdissected thoracic propriospinal neurons at different times after low-thoracic spinal cord transection in adult rats. Propriospinal neurons projecting to the lumbar enlargement were captured at various time points following no lesion or low thoracic spinal cord transection.
Project description:Analysis of expression changes in prelabeled laser-microdissected thoracic propriospinal neurons at different times after low-thoracic spinal cord transection in adult rats.