Abstract
The development of complex stratified epithelial barriers in mammals is initiated from single-layered epithelia. How stratification is initiated and fueled are still open questions. Previous studies on skin epidermal stratification suggested a central role for perpendicular/asymmetric cell division orientation of the basal keratinocyte progenitors. Here, we use centrosomes, that organize the mitotic spindle, to test whether cell division orientation and stratification are linked. Genetically ablating centrosomes from the developing epidermis leads to the activation of the p53-, 53BP1- and USP28-dependent mitotic surveillance pathway causing a thinner epidermis and hair follicle arrest. The centrosome/p53-double mutant keratinocyte progenitors significantly alter their division orientation in the later stages without majorly affecting epidermal differentiation. Together with time-lapse imaging and tissue growth dynamics measurements, the data suggest that the first and major phase of epidermal development is boosted by high proliferation rates in both basal and suprabasally-committed keratinocytes as well as cell delamination, whereas the second phase maybe uncoupled from the division orientation of the basal progenitors. The data provide insights for tissue homeostasis and hyperproliferative diseases that may recapitulate developmental programs.
Highlights
The development of complex stratified epithelial barriers in mammals is initiated from singlelayered epithelia
On a postnatal day 21 (P21), the centrosome mutant mice were smaller than their control littermates and had grossly thin and transparent skin with very sparse hair (Fig. 1e; Supplementary Fig. 1a)
To avoid any secondary complications of centriole loss after birth, we focused most of our analyses on embryonic development until P0
Summary
The development of complex stratified epithelial barriers in mammals is initiated from singlelayered epithelia. Previous studies on skin epidermal stratification suggested a central role for perpendicular/asymmetric cell division orientation of the basal keratinocyte progenitors. From E13.5 onwards, more of the dividing basal progenitors shift their axis of division to a perpendicular orientation, which has become synonymous with an asymmetric division, to generate one daughter progenitor cell that remains in the basal layer, and one differentiated daughter cell that stratifies the forming epidermis[11,12]. Conditional ablation of Sas-4 in the developing brain recapitulates the human microcephaly phenotype and leads to p53-dependent cell death of the radial glial progenitors (RGPs) in the cortex[24] Activation of this p53-dependent pathway is independent of DNA damage or chromosome segregation errors and instead is associated with prolonged mitotic duration[23,24]. Recent reports in cultured mammalian cell lines have confirmed our findings and extended them to include 53BP1 and USP28 as components acting upstream of p53 in a pathway termed “the mitotic surveillance pathway”[25,26,27,28,29,30]
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