Expression of a surfactant protein C mutation links postnatal type 2 cell dysfunction with adult disease
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ABSTRACT: Mutations in the gene encoding surfactant protein C (SFTPC) are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked-in a familial disease-associated SFTPC mutation, L188Q (L184Q in mice), into the mouse Sftpc locus. Expression of L184Q (LQ) resulted in formation of an unstable, misfolded proprotein (proSP-CLQ) that was rapidly degraded by the proteasome pathway. Importantly, expression of misfolded proSP-CLQ was associated with a decrease in AT2 cells in adult mutant mice, with no effect on lung homeostasis; however, lung regeneration in response to bleomycin challenge was substantially reduced in mutant mice. Translation of proSP-CLQ exceeded that of proSP-CWT in neonatal AT2 cells and was associated with activation of oxidative stress and apoptosis leading to impaired expansion of AT2 cells during postnatal alveolarization. Collectively, these data support the hypothesis that susceptibility to disease in adult mutant mice is established during postnatal lung development and is associated with a reduction in AT2 cell numbers.
ORGANISM(S): Mus musculus
PROVIDER: GSE155814 | GEO | 2021/06/30
REPOSITORIES: GEO
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