Fstl1 determines luminal size of mouse trachea through negative regulation of BMP4 signaling

Trachea is a wide tube with smooth luminal epithelia that enables efficient ventilation. In this study, we provide the evidence that the mitotic angles of most tracheal epithelial cells exhibit ordered and transverse orientations, which allows the tracheal lumen to grow along the anterior-posterior (AP) axis, with its circumference being higher than length. We show that the BMP4 signaling antagonist follistatin-like 1 (Fstl1) is a critical regulator for tracheal morphogenesis. Mice with Fstl1 deletion exhibit wider trachea with enlarged lumen as a result of the increased proportion of mitotic cells with their spindles nearly vertical to the tracheal longitudinal axis. Mechanistically, Fstl1 regulates BMP4 signaling by antagonizing p-Smad1/5/8 in tracheal epithelial cells. Reducing BMP4 signaling activity rescues lumen enlargement and normalizes the spindle angle distribution in Fstl1-deficient tracheas. Therefore, we provide evidence to demonstrate that Fstl1 modulates the oriented cell division and tracheal morphogenesis, in part, through BMP4 signaling.