title: Programmed cell-to-cell variability in Ras activity triggers emergent behaviors during mammary epithelial morphogenesis.
abstract: Variability in signaling pathway activation between neighboring epithelial cells can arise from local differences in the microenvironment, noisy gene expression, or acquired genetic changes. To investigate the consequences of this cell-to-cell variability in signaling pathway activation on coordinated multicellular processes such as morphogenesis, we use DNA-programmed assembly to construct three-dimensional MCF10A microtissues that are mosaic for low-level expression of activated H-Ras. We find two emergent behaviors in mosaic microtissues: cells with activated H-Ras are basally extruded or lead motile multicellular protrusions that direct the collective motility of their wild-type neighbors. Remarkably, these behaviors are not observed in homogeneous microtissues in which all cells express the activated Ras protein, indicating that heterogeneity in Ras activity, rather than the total amount of Ras activity, is critical for these processes. Our results directly demonstrate that cell-to-cell variability in pathway activation within local populations of epithelial cells can drive emergent behaviors during epithelial morphogenesis.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Liu
authors.forename: Justin T
authors.initials: JT
authors.lastname: Farlow
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Paulson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Labarge
authors.forename: Zev J
authors.initials: ZJ
authors.lastname: Gartner
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D002465:Cell Movement; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D042361:Mammary Glands, Human / Q000254:growth & development; D009024:Morphogenesis; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018631:ras Proteins