Asymmetric Cell Divisions Promote Notch-Dependent Epidermal Differentiation

Stem and progenitor cells utilize asymmetric cell divisions to balance proliferation and differentiation. Evidence from lower eukaryotes shows that this process is regulated by proteins asymmetrically distributed at the cell cortex during mitosis: (1) Par3-Par6-aPKC, conferring polarity; (2) Gαi-LGN/AGS3-NuMA-p150(glued), governing spindle positioning. Here, we focus on developing mouse skin, where progenitors execute a switch from predominantly symmetric to asymmetric divisions concomitant with stratification. Using in vivo skin-specific lentiviral RNAi, we investigate spindle orientation regulation and provide direct evidence that LGN, Numa1 and 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 RNAi 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.