Prominin‐1 controls stem cell activation by orchestrating ciliary dynamics. (6th December 2018) - Singer, Donald
Abstract: Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly–disassembly dynamics are under rigid cell cycle‐dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol‐binding membrane glycoprotein, Prominin‐1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases. Synopsis: Using the continuously growing mouse incisor tooth as a model for stem cell activation, primary cilia are shown to function at the onset of differentiation. The stem cell surface marker prominin‐1 (Prom1, CD133) is required for sequential recruitment of ciliary components and coordination with sonic hedgehog (SHH) signalling, shedding new light on how stem cell state and differentiation are balanced. Mouse incisor tooth epithelial stem cells and transit‐amplifying cells display distinct, dynamic primary cilia biogenesis. Deletion of the ciliary component IFT88 disrupts stem cell activation in vivo . Prom1 is differentially co‐expressed with ciliary components Arl13b and Hdac6 in stem cells and transit‐amplifying cells, respectively. Prom1 knockout or Lys138 mutation in mice impairs primary cilia biogenesis, quiescent stem cell proliferation, and lineage differentiation. GLIS2 and PROM1 cooperate in nuclei to regulate SHH signaling and its downstream target STAT3. Abstract : The glycoprotein Prom1 has functional roles in stem cell activation and self‐renewal by regulating primary cilia biogenesis and cilia‐associated signaling.