The bundled architecture of actin filaments is not needed for intestinal microvillar morphogenesis, as shown in knockout mice devoid of microvillar actin-bundling proteins. This architecture is essential for the apical anchorage of digestive proteins, probably via the recruitment of key players in apical retention, such as myosin-1a, and, as a result, for intestinal physiology.

Significance Intestinal epithelium damage is common but becomes recurrent in chronic intestinal disorders. Healing implies cell migration, which necessitates extensive cellular reorganization. We demonstrate that intestinal epithelial cells completely disassemble their apical actin-based microvilli upon migration, and we identify the protein villin and its actin-severing function as responsible for this physiological process. We show that this apical pole effacement is required for the acquisition of a motile phenotype and efficient wound healing. These findings demonstrate how intestinal epithelial cells acquired a mechanism at the level of the actin cytoskeleton to convert efficiently from a highly differentiated to a motile polarity.

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Sprouting angiogenesis is fundamental for development and contributes to cancer, diabetic retinopathy, and cardiovascular diseases. Sprouting angiogenesis depends on the invasive properties of endothelial tip cells. However, there is very limited knowledge on how tip cells invade into tissues. Here, we show that endothelial tip cells use dactylopodia as the main cellular protrusion for invasion into nonvascular extracellular matrix. We show that dactylopodia and filopodia protrusions are balanced by myosin IIA (NMIIA) and actin-related protein 2/3 (Arp2/3) activity. Endothelial cell-autonomous ablation of NMIIA promotes excessive dactylopodia formation in detriment of filopodia. Conversely, endothelial cell-autonomous ablation of Arp2/3 prevents dactylopodia development and leads to excessive filopodia formation. We further show that NMIIA inhibits Rac1-dependent activation of Arp2/3 by regulating the maturation state of focal adhesions. Our discoveries establish a comprehensive model of how endothelial tip cells regulate its protrusive activity and will pave the way toward strategies to block invasive tip cells during sprouting angiogenesis.