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Investigation of the gene expression changes triggered by the lung mesenchymal Tsc2KO in each major cell subpopulation of the adult mouse lung

ABSTRACT: Tumor suppressor Tuberous sclerosis complex 2 (TSC2) is a key negative regulator of mammalian target of rapamycin (mTOR), a central controller of cell growth and metabolism in health and disease. Loss of TSC2 induces the constitutive activation of mTORC1 in rare lung disease pulmonary Lymphangioleiomyomatosis (LAM), which affects only women of childbearing age and characterized by lung destruction and progressive loss of pulmonary function. Little is known how TSC2 loss induces LAM and what is the LAM cell of origin. To determine cell-type specific effects of TSC2 loss and mTORC1 activation on lung homeostasis we generated new transgenic mice with targeted Tsc2 deletion in lung mesenchyme Tbx4-Cre+Tsc2flox/flox and lung epithelium Shh-Cre+Tsc2flox/flox. Both Tbx4-Cre+, Tsc2flox/flox and Shh-Cre+, Tsc2flox/flox mice were viable and fertile. Adult Tbx4-Cre+Tsc2flox/flox mice demonstrated mTORC1 activation in lung mesenchyme, progressive alveolar enlargement, female-specific pulmonary function decline and prgenancy-induced lesion growth. To investigate molecular mechanism underlying observed phenotypic changes in the Tsc2KO lungs we performed comparative bulk-RNAseq analysis of the gene expression changes in the major cell subpopulations of the adult female 8-week-old Tsc2KO mouse lungs compared to the age- and sex-matched WT controls.

ORGANISM(S): Mus musculus

PROVIDER: GSE139818 | GEO | 2020/08/31

REPOSITORIES: GEO

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Project description:Two critical events that are required for normal transition from fetal to extrauterine life are development of the alveoli that allow for efficient gas exchange in the lung and relaxation of the pulmonary vascular smooth muscle. Patients with congenital diaphragmatic hernia (CDH) have abnormal lung and pulmonary vascular development that results in a lethal combination of lung hypoplasia and pulmonary hypertension. To better understand the mechanisms responsible for abnormal lung and pulmonary vascular development and function we generated Pbx1/2 conditional knockout mice that lack Pbx1 and Pbx2 expression in the lung mesenchyme. Pbx1 has previously been shown to be required for normal diaphragm development, however its role in alveologenesis, and the mechanisms responsible for pulmonary hypertension, has not been studied. We found that Pbx1/2 CKO mice have failure of alveologenesis and die of severe pulmonary hypertension by 2 to 3 weeks of age. In order to better understand the downstream genetic mis-regulation caused by deletion of Pbx1/2, and identify their potential transcriptional targets, we carried out transcriptional profiling of Pbx1/2 CKO and control mice starting at postnatal day 3 (P3), when a histological phenotype first becomes apparent, and then working back to the time of birth (P0), and embryonic day 14 (E14) when the pulmonary vascular smooth muscle is developing. In this dataset are the expression data obtained from dissected embryonic and early postnatal lungs of Pbx1/2 CKO and control mice. Pbx1/2 CKO mice are homozygous null for Pbx2 with conditional deletion of Pbx1 in the lung mesenchyme directed by Tbx4 Cre (Tbx4 Cre/wild-type; Pbx1 flox/flox; Pbx2 delta/delta). Control mice are homozygous null for Pbx2 and are heterozygous for Pbx1 in the lung mesenchyme (Tbx4 Cre/wild-type; Pbx1 flox/wild-type; Pbx2 delta/delta). These data are used to identify the transcriptional targets and down-stream effectors of PBX transciptional regulation in the lung.

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Investigation of the gene expression changes triggered by the lung mesenchymal Tsc2KO in each major cell subpopulation of the adult mouse lung

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