title: Asymmetric cell divisions promote Notch-dependent epidermal differentiation.
abstract: Stem and progenitor cells use asymmetric cell divisions to balance proliferation and differentiation. Evidence from invertebrates shows that this process is regulated by proteins asymmetrically distributed at the cell cortex during mitosis: Par3-Par6-aPKC, which confer polarity, and Gα(i)-LGN/AGS3-NuMA-dynein/dynactin, which govern spindle positioning. Here we focus on developing mouse skin, where progenitor cells execute a switch from symmetric to predominantly asymmetric divisions concomitant with stratification. Using in vivo skin-specific lentiviral RNA interference, we investigate spindle orientation regulation and provide direct evidence that LGN (also called Gpsm2), NuMA and dynactin (Dctn1) are involved. In compromising asymmetric cell divisions, we uncover profound defects in stratification, differentiation and barrier formation, and implicate Notch signalling as an important effector. Our study demonstrates the efficacy of applying RNA interference in vivo to mammalian systems, and the ease of uncovering complex genetic interactions, here to gain insights into how changes in spindle orientation are coupled to establishing proper tissue architecture during skin development.
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Williams
authors.forename: Slobodan
authors.initials: S
authors.lastname: Beronja
authors.forename: H Amalia
authors.initials: HA
authors.lastname: Pasolli
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D000072159:Dynactin Complex; D000078404:Epidermal Cells; D005260:Female; D055785:Gene Knockdown Techniques; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000196:embryology; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; C502655:LGN protein, mouse; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C489080:Numa1 protein, mouse; D051880:Receptors, Notch