Spindle orientation and epidermal morphogenesis

Abstract

Asymmetric cell divisions (ACDs) result in two unequal daughter cells and are a hallmark of stem cells. ACDs can be achieved either by asymmetric partitioning of proteins and organelles or by asymmetric cell fate acquisition due to the microenvironment in which the daughters are placed. Increasing evidence suggests that in the mammalian epidermis, both of these processes occur. During embryonic epidermal development, changes occur in the orientation of the mitotic spindle in relation to the underlying basement membrane. These changes are guided by conserved molecular machinery that is operative in lower eukaryotes and dictates asymmetric partitioning of proteins during cell divisions. That said, the shift in spindle alignment also determines whether a division will be parallel or perpendicular to the basement membrane, and this in turn provides a differential microenvironment for the resulting daughter cells. Here, we review how oriented divisions of progenitors contribute to the development and stratification of the epidermis.

Keywords: asymmetric cell division; cell fate; spindle orientation; symmetric cell division.

Figure 1.

Epidermal organization. The stratified epidermis consists of basal, spinous and granular layers, and the cornified envelope, assembled upon the basement membrane. Each layer expresses distinct keratin filaments and is receptive to different signalling pathways.

Figure 2.

Balancing stem cell divisions with cell fate. (a) Progenitors in the basal layer of the epidermis can divide asymmetrically to yield two cells that are differentially fated to become a progenitor cell (PC) and a differentiating cell (DC). Alternatively, they can divide symmetrically to produce two cells that both either differentiate, as in (b) or maintain their progenitor fate, as in (c). Asymmetric divisions would maintain tissue balance, as in homeostasis, whereas symmetric divisions would alter the stem cell population within the tissue, as in processes such as ageing, wound healing or hyperproliferative disorders, including cancer.

Figure 3.

Stratification of epidermis through oriented divisions. (a) At early stages of embryonic development, progenitor cells of the epidermis divide with their spindle oriented parallel to the basement membrane. (b) As stratification and differentiation progresses, perpendicular oriented divisions begin to dominate, representing up to 70% of all divisions through these critical stages of embryogenesis. Perpendicular divisions generate a basal progenitor cell and a differentiating cell positioned in the suprabasal layer. These differential cell fate acquisitions define the ACDs of the epidermis.

Figure 4.

Molecular mechanism orienting the mitotic spindle. (a). In Drosophila neuroblasts, Pins interacts with cortical Gα_i and binds to Mud. Mud and Dynein orient the spindle via astral microtubules. LGN also binds to Insc, in a complex with Par3. A second mechanism to orient the spindle has been discovered, in which Aurora A phosphorylates the linker region of Pins to recruit Dlg and Khc73. (b) In epidermal basal cells undergoing ACD, LGN, mInsc, NuMA and Dynactin are recruited to the apical cortex in mitosis, and function in orienting the spindle perpendicular to the basement membrane.