Regulated spindle orientation buffers tissue growth in the epidermis

Abstract

Tissue homeostasis requires a balance between progenitor cell proliferation and loss. Mechanisms that maintain this robust balance are needed to avoid tissue loss or overgrowth. Here we demonstrate that regulation of spindle orientation/asymmetric cell divisions is one mechanism that is used to buffer changes in proliferation and tissue turnover in mammalian skin. Genetic and pharmacologic experiments demonstrate that asymmetric cell divisions were increased in hyperproliferative conditions and decreased under hypoproliferative conditions. Further, active K-Ras also increased the frequency of asymmetric cell divisions. Disruption of spindle orientation in combination with constitutively active K-Ras resulted in massive tissue overgrowth. Together, these data highlight the essential roles of spindle orientation in buffering tissue homeostasis in response to perturbations.

A two-phase model of skin epidermal stratification: lessons from centrosomes

“…During the second phase of epidermal development between E15.5-E17.5, the Sas-4 p53 mutants show a decrease in the fraction of parallel division orientation and an increase in the perpendicular one in basal keratinocyte progenitors that do not lead to a corresponding decrease in basal layer density, or a suprabasal layer thickening ( Fig. 4e-g), as predicted by the model that cell division orientation and epidermal differentiation are coupled 55 . Of note, the increase in cell densities and cell packing defects in both layers of the epidermis in Sas-4 p53 double mutants (Fig.…”

“…In addition, in Sas-4; p53 double mutants, the decrease in the fraction of parallel division orientations and the increase in the perpendicular one in basal keratinocyte progenitors do not lead to a corresponding decrease in basal layer density or hyperdifferentiation (Fig. 3D-F), as predicted by the model that cell division orientation and epidermal stratification are coupled 44 . Our data suggest that a perpendicular division of the basal progenitors in the developing skin epidermis does not necessarily result in an asymmetric cell fate.…”

2‐O‐Octadecylascorbic acid represses RhoGDIβ expression and ameliorates DNA damage‐induced abnormal spindle orientations

“…There is an increasing recognition that regulated spindle orientation is important for the maintenance of epithelial homeostasis. Its dysregulation is implicated in the impairment of organ structures and functions, and is related to carcinogenesis 10,30,32–35 . Our previous studies demonstrated that a RhoGDIβ C‐terminal fragment (ΔN‐RhoGDIβ) is persistently expressed in response to X‐irradiation and thereby inhibits Cdc42 activity, which leads to spindle misorientation in the irradiated cells 19 .…”

Orchestration of tissue‐scale mechanics and fate decisions by polarity signalling

“…Comprehensive reviews on polarity proteins and cancer can be found here (Saito et al, 2018;Stephens et al, 2018;Reina-Campos et al, 2019;Fomicheva et al, 2020). Notably, also genetic disruption of spindle orientation (via expression of a NuMA mutant) was recently shown to cooperate with oncogenic KRas in causing strong skin tissue overgrowth (Morrow et al, 2019), further implicating regulated cell division orientation in cancer.…”