New branch formation by budding. (A) New branches can form through two geometrically distinct processes, budding or clefting. Schematics of budding in Drosophila trachea (B) and mouse retina blood vessels (C), where budding occurs by an invasive form of collective migration. The identity of the protrusive tip cell is specified by high RTK signaling. A Delta/Notch-mediated lateral inhibition mechanism prevents follower cells from becoming leader cells. Schematics of budding in mouse mammary gland (D) and the ureteric bud of mouse kidney (E), where budding occurs by a noninvasive form of collective migration and regionalized cell proliferation. The stratified tip of the mammary gland, or TEB, has high FGF receptor (FGFR) activity and higher proliferation rate than the stalk, which contains two cell layers. The tip of the ureteric bud at this early stage is pseudostratified, and its identity is specified by high RET signaling activity. EGFR, EGF receptor; VEGFR, VEGF receptor.