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Abstract

Respiratory Distress Syndrome occurs in preterm births. Premature lungs lack pulmonary surfactant produced by alveolar type II (ATII) cells. Understanding signaling pathways that promote maturation of ATII cells could reduce time spent in neonatal care units. Tcf21, a bHLH transcription factor, is expressed during lung development, and loss of Tcf21 leads to respiratory failure and dysregulation of Wnt signaling. It is hypothesized that lipofibroblasts secrete Wnt ligands to induce ATII cell differentiation. Using genetically engineered mice that permit isolation of ribosomes from Tcf21 lineage cells, the profile of Wnt ligand RNA expressions were determined. To confirm whether Tcf21 is sufficient to stimulate Wnt ligands, Tcf21 was overexpressed in primary lung fibroblasts. The results showed increased expressions of Wnt 2, 2b, 4, and 5a, suggesting that Tcf21 promotes expression of these Wnt ligands. The expression of Wnt by Tcf21 was investigated in vivo by isolating ribosomal associated RNA from Tcf21 control and null cells. The quantitative PCR demonstrated that Wnt2 and 5a were enriched within the lipofibroblast. Furthermore, data from Tcf21 mutant lungs demonstrated a loss of lipofibroblasts with subsequent reduction in ATII cells. The main findings from these studies indicate that lipofibroblasts are necessary for ATII cell differentiation and that Wnt ligands may be involved.

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