RETRACTED: Btbd7 is essential for region-specific epithelial cell dynamics and branching morphogenesis in vivo

Abstract

Branching morphogenesis of developing organs requires coordinated but poorly understood changes in epithelial cell-cell adhesion and cell motility. We report that Btbd7 is a crucial regulator of branching morphogenesis in vivo. Btbd7 levels are elevated in peripheral cells of branching epithelial end buds, where it enhances cell motility and cellcell adhesion dynamics. Genetic ablation of Btbd7 in mice disrupts branching morphogenesis of salivary gland, lung and kidney. Btbd7 knockout results in more tightly packed outer bud cells, which display stronger E-cadherin localization, reduced cell motility and decreased dynamics of transient cell separations associated with cleft formation; inner bud cells remain unaffected. Mechanistic analyses using in vitro MDCK cells to mimic outer bud cell behavior establish that Btbd7 promotes loss of E-cadherin from cell-cell adhesions with enhanced migration and transient cell separation. Btbd7 can enhance E-cadherin ubiquitination, internalization, and degradation in MDCK and peripheral bud cells for regulating cell dynamics. These studies show how a specific regulatory molecule, Btbd7, can function at a local region of developing organs to regulate dynamics of cell adhesion and motility during epithelial branching morphogenesis.

Autocrine inhibition of cell motility can drive epithelial branching morphogenesis in absence of growth

“…Figure 4A shows morphologies for increasing values of T . Consistent with the inhibition or knockout of Btbd7 [48,6] at low values of T the tissue did not branch, because only few random cell protrusions were strong enough to overcome the effect of the chemoinhibitor. For slightly higher cell motility, at cellular temperatures of around T = 20, the tissue developed droplet-like extensions: as soon as one or a few protrusions locally overcame the effect of the inhibitor the curvature locally increased leading to reduced levels of chemoinhibition.…”

“…The previous section showed that the proposed branching mechanism is driven by random cell motility. Interestingly, Btbd7, a positive regulator of epithelial cell motility, is required for branching morphogenesis of salivary glands and the lung [48], and is expressed in branching end buds in a variety of branching epithelial organs [6]. Knock-out of Btbd7 reduces epithelial cell motility in the end buds of submandibular salivary glands, leading to incomplete branching [6].…”

Autocrine inhibition of cell motility can drive epithelial branching morphogenesis in the absence of growth

“…The previous section showed that the proposed branching mechanism is driven by random cell motility. Interestingly, Btbd7, a positive regulator of epithelial cell motility, is required for branching morphogenesis of salivary glands and the lung [46], and is expressed in branching end buds in a variety of branching epithelial organs [47]. Knock-out of Btbd7 reduces epithelial cell motility in the end buds of submandibular salivary glands, leading to incomplete branching [47].…”

Meeting report – Cellular dynamics: membrane–cytoskeleton interface

“…Using techniques, such as particle image velocimetry (PIV) and vector mapping, his group investigated the modes of movement of different cells in 3D matrices. Their more recent work has focused on the role of BTBD7 in regulating adhesion and motility during morphogenesis in epithelial cells (Daley et al, 2017).…”